C Buddy Creech1, Robert W Frenck2, Eric A Sheldon3, David J Seiden4, Martin K Kankam5, Edward T Zito6, Douglas Girgenti7, Joseph M Severs7, Frederick W Immermann7, Lisa K McNeil7, David Cooper7, Kathrin U Jansen7, William Gruber7, Joseph Eiden7, Annaliesa S Anderson7, James Baber8. 1. Vanderbilt Vaccine Research Program, Vanderbilt University School of Medicine, S-2323 MCN, 1161 21st Avenue South, Nashville, TN 37232, United States. Electronic address: Buddy.creech@vanderbilt.edu. 2. Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, United States. 3. Miami Research Associates, 6141 Sunset Dr., South Miami, FL 33143, United States. 4. Broward Research Group, 7261 Sheridan Street, Suite 210, Hollywood, FL 33024, United States. 5. Vince and Associates Clinical Research, 10103 Metcalf Ave, Overland Park, KS 66212, United States. 6. Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, United States. 7. Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States. 8. Pfizer Australia Pty Ltd, Sydney, 38-42 Wharf Rd, West Ryde, NSW 2114, Australia.
Abstract
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.
RCT Entities:
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.
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