Persistence of Immune Responses Through 36 Months in Healthy Adults After Vaccination With a Novel Staphylococcus aureus 4-Antigen Vaccine (SA4Ag)

Abstract

Background: Staphylococcus aureus causes serious health care- and community-associated disease, requiring improved preventive measures such as vaccines. The investigational S. aureus 4-antigen vaccine (SA4Ag), comprising capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to CRM197, recombinant mutant clumping factor A (rmClfA), and recombinant manganese transporter protein C (rP305A or rMntC), was well tolerated, inducing robust functional immune responses to all 4 antigens through 12 months postvaccination. This is a serological extension study through 36 months postvaccination.

Methods: In 2 previous studies, healthy adults received SA4Ag, SA3Ag (without rMntC), or placebo; serology was also assessed at ~24 and ~36 months postvaccination. Functional immune responses (antibody responses that facilitate killing of S. aureus or neutralize S. aureus virulence mechanisms) were assessed with opsonophagocytic activity killing assays (CP5 or CP8) and a fibrinogen-binding inhibition assay (ClfA). A competitive Luminex immunoassay assessed ClfA and rMntC responses. Adverse events within 48 hours of blood draw were recorded.

Results: Four hundred forty subjects (18-64 years old, 255; 65-85 years old, 185) were enrolled. At 24 and 36 months postvaccination, subjects receiving SA4Ag had substantially higher geometric mean titers (GMTs) for CP5, CP8, and ClfA vs baseline; geometric mean fold rises (GMFRs) from baseline to month 36 were 2.7-8.1. For rMntC, 36-month GMTs declined from peak levels but remained above baseline for all SA4Ag groups; GMFRs from baseline to month 36 were 1.8 and 1.5 in the younger and older cohorts, respectively.

Conclusions: Persistent functional immune responses to S. aureus antigens were observed through 36 months in healthy adults.

Clinicaltrialsgov: NCT01643941 and NCT01364571.

Keywords: SA4Ag; Staphylococcus aureus; orthopedic infections; vaccine; vaccine immunogenicity persistence.

© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.

Immunogenicity results in the evaluable immunogenicity population.a A, The younger cohort (18–64 years of age). B, The older cohort (65–85 years of age). aThe evaluable immunogenicity population included all subjects who were eligible, had no confirmed Staphylococcus aureus infection since completion of the primary study, had blood drawn within the protocol-specified time frame, had valid and determinate assay results for the proposed analysis, and had no major protocol deviations. bVaccine groups labeled low-dose, mid-dose, and high-dose SA4Ag refer only to differences in rMntC levels (20 μg, 60 μg, and 200 μg, respectively). CP5-CRM197, CP8-CRM197, and rmClfA levels (30 μg, 30 μg, and 60 μg, respectively) are the same in each SA4Ag dose level and in SA3Ag. Abbreviations: ClfA, surface protein clumping factor A; cLIA, competitive Luminex immunoassay; CP5, capsular polysaccharide serotype 5; CP8, capsular polysaccharide serotype 8; FBI, fibrinogen-binding inhibition; OPA, opsonophagocytic activity; rMntC, recombinant manganese transporter protein C; SA3Ag, Staphylococcus aureus 3-antigen vaccine; SA4Ag, S. aureus 4-antigen vaccine.

Figure 2.

Percentage of subjects achieving predefined antibody thresholds at month 36 postvaccination in the evaluable immunogenicity population.a Error bars indicate 95% confidence intervals for each value. Younger cohort: 18–64 years of age; older cohort: 65–85 years of age. aThe evaluable immunogenicity population included all subjects who were eligible, had no confirmed Staphylococcus aureus infection since completion of the primary study, had blood drawn within the protocol-specified time frame, had valid and determinate assay results for the proposed analysis, and had no major protocol deviations. bVaccine groups labeled low-dose, mid-dose, and high-dose SA4Ag refer only to differences in rMntC levels (20 μg, 60 μg, and 200 μg, respectively). CP5-CRM197, CP8-CRM197, and rmClfA levels (30 μg, 30 μg, and 60 μg, respectively) are the same in each SA4Ag dose level and in SA3Ag. cFor rMntC, the threshold for cLIA results was set at the lower limit of quantitation of the assay, which was determined based on assay linearity and precision; this threshold is relatively low, and thus the immune responses elicited by rMntC were not able to be detected due to the high proportions of participants with assay results above the threshold. Abbreviations: ClfA, surface protein clumping factor A; cLIA, competitive Luminex immunoassay; CP5, capsular polysaccharide serotype 5; CP8, capsular polysaccharide serotype 8; FBI, fibrinogen-binding inhibition; OPA, opsonophagocytic activity; rMntC, recombinant manganese transporter protein C; SA3Ag, Staphylococcus aureus 3-antigen vaccine; SA4Ag, S. aureus 4-antigen vaccine.