VLP-based vaccine induces immune control of Staphylococcus aureus virulence regulation

Abstract

Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) and mounting antibiotic resistance requires innovative treatment strategies. S. aureus uses secreted cyclic autoinducing peptides (AIPs) and the accessory gene regulator (agr) operon to coordinate expression of virulence factors required for invasive infection. Of the four agr alleles (agr types I-IV and corresponding AIPs1-4), agr type I isolates are most frequently associated with invasive infection. Cyclization via a thiolactone bond is essential for AIP function; therefore, recognition of the cyclic form of AIP1 may be necessary for antibody-mediated neutralization. However, the small sizes of AIPs and labile thiolactone bond have hindered vaccine development. To overcome this, we used a virus-like particle (VLP) vaccine platform (PP7) for conformationally-restricted presentation of a modified AIP1 amino acid sequence (AIP1S). Vaccination with PP7-AIP1S elicited AIP1-specific antibodies and limited agr-activation in vivo. Importantly, in a murine SSTI challenge model with a highly virulent agr type I S. aureus isolate, PP7-AIP1S vaccination reduced pathogenesis and increased bacterial clearance compared to controls, demonstrating vaccine efficacy. Given the contribution of MRSA agr type I isolates to human disease, vaccine targeting of AIP1-regulated virulence could have a major clinical impact in the fight against antibiotic resistance.

Vaccination with VLPs Presenting a Linear Neutralizing Domain of S. aureus Hla Elicits Protective Immunity

“…To assess the efficacy of our VLP-LND vaccines, we used a well-established mouse model of S. aureus skin infection/intoxication, where formation of a necrotic lesion is Hla-dependent [ 10 , 19 , 20 , 21 ]. In this model, the necrotic lesion visibly forms on the skin surface and lesion size is easily measurable [ 22 , 23 , 24 , 25 , 26 ], allowing straightforward assessment of Hla vaccine efficacy. Mice were immunized with two doses of AP205-LND or Qβ-LND VLPs.…”

“…Expression strains of both AP205 and AP205-LND were grown overnight on media with kanamycin and used to inoculate a 50 to 500 mL culture with shaking. When OD 600 nm surpassed 0.6, the culture was induced with 0.2% w/v arabinose and incubated for an additional 3 h. The cells were pelleted by centrifugation and purified via FPLC and confirmed for purity as previously described [ 25 ].…”

Recent Advances in Anti-virulence Therapeutic Strategies With a Focus on Dismantling Bacterial Membrane Microdomains, Toxin Neutralization, Quorum-Sensing Interference and Biofilm Inhibition

“…In addition, using a murine model of S. aureus SSTI (skin and soft tissue infection), it was observed that after a challenge with a virulent S. aureus USA300 isolate LAC ( agr -type I), in PP7-AIP1S immunized mice reduced agr -type I-mediated pathogenesis was developed, compared to the non-immunized animals. Reduced alpha-hemolysin levels, as well as RNAIII transcription at the infection site in the immunized animals, together with the in vitro antibodies binding (from immunized animals) to AIP1 suggested the occurrence of immune suppression of agr -signaling during the infection (Daly et al, 2017). Using a peptide library displayed on VLP, O'Rourke et al (2014) identified eight peptides (VLP-peptides) that bind specifically to the antigen-binding site of the monoclonal antibody AP4-24H11.…”

Virus-like Particle-Based L2 Vaccines against HPVs: Where Are We Today?

“…Not only can VLPs be used to develop vaccines against the virus from which the structural proteins are derived from, they can also be used as platforms to display heterologous antigens from other viruses [53], bacteria [54], pathophysiological diseases like cholesterol [55], and even tumor-associated antigens [56]. The goal of a chimeric VLP is to induce antibodies against a heterologous antigen displayed on the platform, but not against the platform.…”