Abstract
Staphylococcus aureus causes a chronic, contagious disease of the udder, or mastitis, in dairy cows. This infection is often refractory to antibiotic treatment, and has a significant economic impact on milk production worldwide. An effective vaccine to prevent S. aureus mastitis would improve animal health, reduce antibiotic dependence and inform human vaccine approaches. The iron-regulated surface determinant A (IsdA) and clumping factor A (ClfA) are conserved S. aureus extracellular-matrix adhesins and target vaccine antigens. Here we report the results of two bovine immunogenicity trials using purified IsdA and ClfA-cholera toxin A2/B chimeras (IsdA-CTA2/B and ClfA-CTA2/B). Cows were intranasally inoculated with IsdA-CTA2/B + ClfA-CTA2/B at dry off and followed for 70 days. Trial 1 utilized three groups with one or two booster doses at a total concentration of 600 or 900 μg. Trial 2 utilized two groups with one booster at a total concentration of 1200 μg. Humoral immune responses in serum and milk were examined by ELISA. Responses in serum were significant between groups and provide evidence of antigen-specific IgG induction after vaccination in both trials. Cellular proliferation was detected by flow cytometry using antigen-stimulated PBMCs from day 60 of Trial 2 and revealed an increase in CD4+ T cells from vaccinated cows. IsdA and ClfA stimulation induced IL-4 expression, but not IFN-γ or IL-17, in PBMCs from day 60 as determined by cytokine expression analysis. Opsonophagocytosis of S. aureus confirmed the functional in vitro activity of anti-IsdA antibodies from Trial 2 serum and milk. The vaccine was well tolerated and safe, and results support the potential of mucosally-delivered CTA2/B chimeras to protect cows from mastitis caused by S. aureus.
Keywords:
Bovine; Mastitis; Staphylococcus; Vaccine.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Intranasal
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Animals
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Antibodies, Bacterial / biosynthesis*
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Antibodies, Bacterial / blood
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Antigens, Bacterial / administration & dosage
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Antigens, Bacterial / genetics
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Antigens, Bacterial / immunology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / microbiology
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Cattle
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Cell Proliferation / drug effects
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Cholera Toxin / administration & dosage
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Cholera Toxin / genetics
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Cholera Toxin / immunology
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Coagulase / administration & dosage
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Coagulase / genetics
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Coagulase / immunology
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Female
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Gene Expression
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Immunity, Humoral / drug effects
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Immunization, Secondary / methods
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Immunogenicity, Vaccine
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Immunoglobulin G / biosynthesis
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Immunoglobulin G / blood
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Interleukin-4 / biosynthesis
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Interleukin-4 / metabolism
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Mammary Glands, Animal / immunology
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Mammary Glands, Animal / microbiology
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Mastitis, Bovine / immunology
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Mastitis, Bovine / microbiology
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Mastitis, Bovine / prevention & control*
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Milk / chemistry
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Milk / immunology
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Milk / microbiology
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Protein Isoforms / administration & dosage
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Protein Isoforms / genetics
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Protein Isoforms / immunology
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology*
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Staphylococcal Infections / immunology
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Staphylococcal Infections / microbiology
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Staphylococcal Infections / prevention & control*
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Staphylococcal Infections / veterinary*
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Staphylococcal Vaccines / administration & dosage
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Staphylococcal Vaccines / biosynthesis*
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Staphylococcal Vaccines / genetics
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / immunology
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Staphylococcus aureus / pathogenicity
Substances
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Antibodies, Bacterial
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Antigens, Bacterial
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ClfA protein, Staphylococcus aureus
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Coagulase
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Immunoglobulin G
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IsdA protein, Staphylococcus aureus
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Protein Isoforms
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Recombinant Fusion Proteins
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Staphylococcal Vaccines
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Interleukin-4
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Cholera Toxin