Safety, tolerability, and immunogenicity of a novel 4-antigen Staphylococcus aureus vaccine (SA4Ag) in healthy Japanese adults

Abstract

A novel Staphylococcus aureus 4-antigen vaccine (SA4Ag) is under development, comprising capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to CRM, recombinant protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (MntC). We evaluated SA4Ag safety, tolerability, and immunogenicity in Japanese adults aged 20 to 64 and 65 to 85 years. A total of 136 healthy Japanese adults (68 per age group) were randomized 1:1 to receive single-dose SA4Ag or placebo intramuscularly (Day 1). Safety assessments included reactogenicity and adverse events. The ability of the vaccine to induce immune responses that are considered functional due to their ability to facilitate the killing of S. aureus or neutralize S. aureus virulence mechanisms was assessed using 5 different antigen-specific assays. SA4Ag was well tolerated in both age groups, with no safety concerns. At Day 29, > 85% of SA4Ag recipients in each age group achieved predefined thresholds for each antigen. Antibody geometric mean-fold rises from baseline to Day 29 in SA4Ag groups were: > 80 and > 30 for CP5 and CP8 (opsonophagocytic activity assay), > 10 for ClfA (fibrinogen-binding inhibition assay), and > 15 and > 7 for ClfA and MntC (competitive Luminex® immunoassay), respectively. Antibody titers decreased through Month 12 but remained well above baseline and placebo levels. SA4Ag had an acceptable safety profile and induced rapid and robust functional immune responses in both age groups. These results support ongoing development of SA4Ag for the prevention of invasive S. aureus disease in elective-surgery patients in Japan, North America, and Europe.

IBT-V02: A Multicomponent Toxoid Vaccine Protects Against Primary and Secondary Skin Infections Caused by Staphylococcus aureus

“…Opsonic antibodies represent a reliable correlate of protection for several other vaccines such as pneumococcal, meningococcal and H. influenzae vaccines (7). Remarkably, all the SA vaccines advanced into clinic were strong inducers of antibodies that promoted opsonophagocytic activity (8)(9)(10), putting in question whether the paradigm of opsonic antibodies as correlate of immunity can be applied to SA. In the case of one of these vaccine candidates, the single component vaccine consisting of the iron-regulated protein IsdB (V710, Merck), the trial was stopped due to safety concerns after ∼8,000 patients undergoing cardiothoracic surgery were recruited.…”

The Candidate Antigens to Achieving an Effective Vaccine against Staphylococcus aureus

“…Besides, a recent study showed that SA4Ag leads to persistent functional immune responses against S. aureus antigens throughout 36 months in healthy adults [39]. Also, further investigation showed that SA4Ag showed an acceptable safety profile and induced rapid and robust functional immune responses in the 20 to 64 and 65 to 85 years groups [40]. This vaccine also showed good results against the progressive condition of S. aureus infection in an animal study.…”

Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies

“…The most noteworthy of these is the phase IIb failure of Pfizer's SA4Ag vaccine candidate. Composed of recombinant MntC, ClfA and both CP5 and CP8, each conjugated to a detoxified form of diphtheria toxin, this vaccine was tested in four phase I clinical trials (20,(139)(140)(141) before ultimately failing to reach designated protection endpoints in a subsequent efficacy trial (NCT02388165). In phase I trials, a single dose of vaccine was sufficient to elicit high titers of specific and functional antibody responses in recipients from age 18-80 shown to last for at least a year after vaccination.…”