James Baber

A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults

BACKGROUND Neisseria meningitidis serogroup B (MnB) is a leading cause of bacterial meningitis and septicemia in adolescents and young adults. No currently licensed and available vaccine has been shown to provide broad protection against endemic MnB disease. A bivalent rLP2086 vaccine based on two factor H-binding proteins (fHBPs) has been developed to provide broad protection against MnB disease-causing strains. METHODS This study assessed the safety and immunogenicity of the final formulation of a bivalent rLP2086 vaccine in 60 healthy adults (18-40 years of age) receiving 120 μg doses at 0, 1, and 6 months. Safety was assessed by collecting solicited reactogenicity data and participant-reporting of adverse events. Immunogenicity was evaluated by human serum bactericidal assay (hSBA) against 5 MnB strains expressing distinct fHBP variants and fHBP-specific immunoglobulin G titre. RESULTS After each immunisation, local reactions such as pain at the injection site and erythema were generally mild or moderate. The most common vaccine-related adverse event was upper respiratory tract infection, which was reported by two participants. Seroprotection (hSBA titres ≥ 1:4) was achieved in 94.3% of participants against a MnB strain expressing the vaccine-homologous fHBP variant A05 and 70.0%-94.7% against MnB strains expressing the heterologous fHBP variants B02, A22, B44, and B24. Seroconversion rates (≥ 4-fold rise in hSBA titres) ranged from 70.0% to 94.7% across the five MnB test strains following the 3-dose vaccination regimen. Immunogenicity responses tended to increase upon subsequent vaccine doses. CONCLUSIONS Bivalent rLP2086 is a promising vaccine candidate for broad protection against MnB disease-causing strains.

A randomized phase I study of the safety and immunogenicity of three ascending dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults

BACKGROUND Staphylococcus aureus is a common cause of healthcare-acquired morbidity and mortality and increased healthcare resource utilization. A prophylactic vaccine is being developed that may reduce this disease burden. METHODS Volunteers in good general health aged 50-85 (n=312) and 18-24 (n=96) years were randomized to receive a single intramuscular dose of one of three dose levels of a non-adjuvanted, 3-antigen S. aureus vaccine (SA3Ag) or placebo. SA3Ag antigens included capsular polysaccharides 5 and 8 (CP5 and CP8), each conjugated to cross-reactive material 197 (CRM197), and recombinant clumping factor A (ClfA). Safety, tolerability, and immunogenicity were evaluated. RESULTS At day 29 post-vaccination, robust immune responses were observed in both age cohorts at all three SA3Ag dose levels. In the primary analysis population, the 50- to 85-year age stratum, geometric mean-fold-rises in competitive Luminex(®) immunoassay antibody titers from baseline ranged from 29.2 to 83.7 (CP5), 14.1 to 31.0 (CP8), and 37.1 to 42.9 (ClfA), all (P<0.001) exceeding the pre-defined two-fold rise criteria. Similar rises in opsonophagocytic activity assay titers demonstrated functionality of the immune response. Most injection-site reactions were mild in severity and there were no substantial differences (SA3Ag vs. placebo) with regard to systemic or adverse events. CONCLUSIONS In this study of healthy adults aged 50-85 and 18-24 years, SA3Ag elicited a rapid and robust immune response and was well tolerated, with no notable safety concerns.

Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised, placebo-controlled phase 1/2 study

BACKGROUND A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. METHODS In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18-64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). RESULTS A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11-15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. CONCLUSIONS Single-dose vaccination of SA4Ag in healthy adults aged 18-64years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. TRIAL REGISTRATION NUMBER NCT01364571.

Safety, tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: Results of a randomised trial

BACKGROUND The decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18-64years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM197) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted. METHODS In this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65-85years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays. RESULTS The results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels. CONCLUSIONS Single-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65-85years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85years. TRIAL REGISTRATION NUMBER NCT01643941.

Vaccine development to prevent Staphylococcus aureus surgical-site infections

Staphylococcus aureus surgical‐site infections (SSIs) are a major cause of poor health outcomes, including mortality, across surgical specialties. Despite current advances as a result of preventive interventions, the disease burden of S. aureus SSI remains high, and increasing antibiotic resistance continues to be a concern. Prophylactic S. aureus vaccines may represent an opportunity to prevent SSI.

The development of a staphylococcus aureus four antigen vaccine for use prior to elective orthopedic surgery

ABSTRACT Staphylococcus aureus (S. aureus) is a challenging bacterial pathogen which can cause a range of diseases, from mild skin infections, to more serious and invasive disease including deep or organ space surgical site infections, life-threatening bacteremia, and sepsis. S. aureus rapidly develops resistance to antibiotic treatments. Despite current infection control measures, the burden of disease remains high. The most advanced vaccine in clinical development is a 4 antigen S. aureus vaccine (SA4Ag) candidate that is being evaluated in a phase 2b/3 efficacy study in patients undergoing elective spinal fusion surgery (STaphylococcus aureus suRgical Inpatient Vaccine Efficacy [STRIVE]). SA4Ag has been shown in early phase clinical trials to be generally safe and well tolerated, and to induce high levels of bactericidal antibodies in healthy adults. In this review we discuss the design of SA4Ag, as well as the proposed clinical development plan supporting licensure of SA4Ag for the prevention of invasive disease caused by S. aureus in elective orthopedic surgical populations. We also explore the rationale for the generalizability of the results of the STRIVE efficacy study (patients undergoing elective open posterior multilevel instrumented spinal fusion surgery) to a broad elective orthopedic surgery population due to the common pathophysiology of invasive S. aureus disease and commonalties of patient and procedural risk factors for developing postoperative S. aureus surgical site infections.