Vaccines for Staphylococcus aureus and Target Populations

Abstract

Staphylococcus aureus is a leading pathogen in surgical site, intensive care unit, and skin infections, as well as healthcare-associated pneumonias. These infections are associated with an enormous burden of morbidity, mortality, and increase of hospital length of stay and patient cost. S. aureus is impressively fast in acquiring antibiotic resistance, and multidrug-resistant strains are a serious threat to human health. Due to resistance or insufficient effectiveness, antibiotics and bundle measures leave a tremendous unmet medical need worldwide. There are no licensed vaccines on the market despite the significant efforts done by public and private initiatives. Indeed, vaccines tested in clinical trials in the last two decades have failed to show efficacy. However, they targeted single antigens and contained no adjuvants and efficacy trials were performed in severely ill subjects. Herein, we provide a comprehensive evaluation of potential target populations for efficacy trials taking into account key factors such as population size, incidence of S. aureus infection, disease outcome, primary endpoints, as well as practical advantages and disadvantages. We describe the whole-blood assay as a potential surrogate of protection, and we show the link between phase III clinical trial data of failed vaccines with their preclinical observations. Finally, we give our perspective on how new vaccine formulations and clinical development approaches may lead to successful S. aureus vaccines.

A small membrane protein critical to both the offensive and defensive capabilities of Staphylococcus aureus

“…Vaccination, for example has been successfully used to control and reduce the incidence of many bacterial infections. However, despite significant investment and multiple diverse S. aureus components including toxins, surface expressed proteins and capsule being targeted, vaccines have provided no significant level protection when used in human trials 31 . Recent studies on populations of clinical isolates may provide an answer to some of these failures, where significant variability in the expression of toxins and capsule has been demonstrated 12-14,32 .…”

PilVax, a novel Lactococcus lactis‐based mucosal vaccine platform, stimulates systemic and mucosal immune responses to Staphylococcus aureus

“…24,25 The potential of several cell wallanchored proteins or immunogenic epitopes thereof including ClfA, 26 ClfB, 24 iron-regulated surface protein A, 27,28 IsdB 29 and fibronectin-binding protein (FnBP) 30,31 for mucosal vaccination has been demonstrated in rodent challenge models. Several leading S. aureus vaccine candidates currently in clinical trials comprise multiple components, covering several different aspects of S. aureus virulence, including cell wall-anchored proteins (reviewed in Pozzi et al 32 and Missiakas and Schneewind 33 ). A current limitation of the PilVax platform is that only short linear epitopes containing <50 amino acids have been successfully introduced without disrupting pilus polymerization and formation on the surface of L. lactis.…”

“…A current limitation of the PilVax platform is that only short linear epitopes containing <50 amino acids have been successfully introduced without disrupting pilus polymerization and formation on the surface of L. lactis. Therefore FnBP was chosen as a suitable target because it contains several wellcharacterized conserved linear B-cell epitopes reported to stimulate antibodies that inhibit binding of S. aureus to fibronectin, including an FnBPA/B epitope (FnBP-10) 34 and two peptide sequences that target FnBPA [D1 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) and D3 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) ]. 35 This study aimed to determine whether selected linear B-cell epitopes from S. aureus FnBPA could be successfully engineered into an L. lactis PilVax strain and used as a mucosal vaccine to stimulate production of a robust local antibody response in the nasal and intestinal mucosa.…”

“…This strategy elicited systemic and mucosal antibody responses to a model antigen after intranasal immunization, but has not been tested for its capacity to stimulate protective mucosal immunity. A well-characterized linear B-cell epitope, D3 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) , from the fibronectin-binding protein A of Staphylococcus aureus was successfully introduced into PilVax and delivered intranasally to mice. Specific antipeptide immunoglobulin (Ig) G and IgA antibodies were detected in the serum and respiratory mucosa of vaccinated mice.…”

Suppression of Staphylococcus aureus virulence by a small-molecule compound

“…An array of virulence factors, including hemolysins, leukocidins, immunemodulatory factors, and exoenzymes, work in concert and contribute to the virulent properties of S. aureus (4). As there are no vaccines available on the market yet and attempts to develop such interventions are not yet successful (5), virulence suppression presents an alternative approach for combating S. aureus infection (6,7).…”