Optimal adjuvant/antigen formulation toward a Staphylococcus aureus human vaccine

Project Summary / abstract: Staphylococcus aureus is a commensal of the human skin and an invasive pathogen, as well as the leading cause of skin and soft tissue infections (SSTI) or sepsis in the United States. S. aureus has developed resistance against all known antibiotics. S. aureus infection is not associated with the development of immunity and, even with surgical and antibiotic therapy, recurrent infections occur in up to 30% of patients. Therefore, the development of a vaccine or immune therapeutic that prevents S. aureus SSTI, bacteremia, sepsis, or that improves the outcome of standard-of-care therapies, or that reduces the incidence of recurrent infections is of high importance. The immune evasive properties of S. aureus are primarily mediated by staphylococcal protein A (SpA), a surface protein that binds immunoglobulin (Ig) thereby preventing opsonophagocytic killing (OPK) by immune cells and suppression of host adaptive immune responses. Our lead vaccine is SpA*, a fully detoxified fragment of SpA which when adjuvanted with aluminum hydroxide (Alum) elicits immune responses that can prevent and reduce nasopharyngeal colonization of S. aureus and invasive S. aureus diseases. Alum drives primarily TH2-effector responses and is included in many FDA approved vaccines but several studies have suggested that stimulating a broad TH1 / TH17 immune response may be required for vaccine protection against the wide range of diseases caused by S. aureus. Therefore, the goal of this phase I proposal is the development of clinical adjuvant formulations that broadly stimulate SpA-specific humoral and cellular immune responses in animals. In specific aim 1 we will establish a clinical adjuvant that stimulates effective TH1 / TH17 cellular and TH2 humoral immune responses against SpA* antigen in mice, rabbits, and guinea pigs. Specific aim 2 will characterize the quality of the humoral vaccine responses generated against adjuvanted SpA* in sera from vaccinated animals by developing assays that measure SpA-neutralizing activity and ability to promote OPK of S. aureus. These studies are critical for determining the value of SpA-specific antibody titers required in vaccinated subjects to promote OPK of S. aureus and neutralization of SpAandapos;s Ig-binding activity. Phase II studies will be designed to cGMP manufacture the vaccine and demonstrate protective efficacy of the lead vaccine formulation in guinea pig and rabbit models of MRSA diseases in support of clinical testing.Public Health Relevance Statement: MRSA, antibiotic-resistant S. aureus, is the most frequent cause of infectious disease mortality in the United States, however a licensed vaccine that can prevent staphylococcal diseases or improve their outcome is not available. The development of vaccines or immune therapeutics against S. aureus addresses an urgent health need and would represent a breakthrough advance in infectious disease therapy.