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

Abstract

The pore-forming cytotoxin α-hemolysin, or Hla, is a critical Staphylococcus aureus virulence factor that promotes infection by causing tissue damage, excessive inflammation, and lysis of both innate and adaptive immune cells, among other cellular targets. In this study, we asked whether a virus-like particle (VLP)-based vaccine targeting Hla could attenuate S. aureus Hla-mediated pathogenesis. VLPs are versatile vaccine platforms that can be used to display target antigens in a multivalent array, typically resulting in the induction of high titer, long-lasting antibody responses. In the present study, we describe the first VLP-based vaccines that target Hla. Vaccination with either of two VLPs displaying a 21 amino-acid linear neutralizing domain (LND) of Hla protected both male and female mice from subcutaneous Hla challenge, evident by reduction in lesion size and neutrophil influx to the site of intoxication. Antibodies elicited by VLP-LND vaccination bound both the LND peptide and the native toxin, effectively neutralizing Hla and preventing toxin-mediated lysis of target cells. We anticipate these novel and promising vaccines being part of a multi-component S. aureus vaccine to reduce severity of S. aureus infection.

Evolution of Vaccines Formulation to Tackle the Challenge of Anti-Microbial Resistant Pathogens

“…Protection against infection was provided by both the SAPNs carrying the Hla antigen and was evaluated by measuring the induction of IgG antibodies and the protection against subcutaneous infection in immunised mice. Both the nanoparticles provided a significant IgG titre response and a reduction of the size of skin lesions, providing encouraging results for the exploitation of these platforms not only against viral but also AMR pathogen infections [113]. In a second example, a synthetic carbohydrate anti-Salmonella enteritidis vaccine was conjugated with bacteriophage Qβ.…”

Self-Assembling Protein Nanoparticles in the Design of Vaccines: 2022 Update

“…The linear neutralizing domains of Hla (LND), of about 21 amino acids long [82], are involved in Hla heptamerisation and it has been shown that an antibody against this epitope can neutralize Hla activity. Using constructs derived from the bacteriophage Qβ and AP205 (bacteriophage coat protein) Joyner and colleagues generated LND SAPNs in E. coli [39] Neutralization experiments showed that antibodies elicited via immunization prevented lysis of Jurkat cells in vitro and conferred protection to mice, with a reduction in both tissue damage and presence of neutrophils. In addition, these antibodies were found to bind to the native toxin and the LND peptide, suggesting high specificity.…”

Staphylococcus aureus Toxins: Promoter or Handicap during Infection?

“…This method aims to develop a therapeutic regime to not only eliminate bacteria, but also reduce their virulence [ 37 ]. Joyner et al developed a virus-based vaccine that target S. aureus toxin (Hla) and attenuates S. aureus Hla-mediated pathogenesis [ 38 ]. This approach could be part of a multi-component S. aureus vaccine in future.…”