Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 51; pp. E5555 - E5563
• Main Authors: Yeaman, Michael R, Filler, Scott G, Chaili, Siyang, Barr, Kevin, Wang, Huiyuan, Kupferwasser, Deborah, Hennessey, Jr, John P, Fu, Yue, Schmidt, Clint S, Edwards, Jr, John E, Xiong, Yan Q, Ibrahim, Ashraf S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.12.2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Adaptive Immunity; Animals; Antigens; Bacterial Vaccines - therapeutic use; Biological Sciences; Comparative analysis; Disease Models, Animal; Glycoproteins; Interleukin-17 - metabolism; Interleukin-22; Interleukins - metabolism; Mice; PNAS Plus; Skin Diseases, Bacterial - therapy; Staphylococcal Infections - prevention & control; Staphylococcus aureus; Staphylococcus infections; T cell receptors; T-Lymphocytes - immunology; Vaccines; skin; vaccine; Th22; Th17; Staphylococcus aureus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1415610111

Significance Staphylococcus aureus is an opportunistic pathogen of the normal human flora. It is among the most frequent causes of cutaneous abscesses, leading to life-threatening invasive infection. Incomplete understanding of host defenses against S. aureus skin or invasive infection has hindered development of effective vaccines to address these issues. NDV-3 is a unique cross-kingdom vaccine targeting S. aureus and Candida albicans . The present studies offer important new evidence: ( i ) NDV-3 protects against methicillin-resistant S. aureus skin and skin structure infection largely through IL-22– and IL-17A–mediated host defense peptide and neutrophil induction, ( ii ) vaccine-mediated IL-22 and IL-17A play distinct roles in protection against cutaneous versus invasive infection, and ( iii ) NDV-3 vaccine efficacy in this model involves a coordinated induction of innate and adaptive immunity. Increasing rates of life-threatening infections and decreasing susceptibility to antibiotics urge development of an effective vaccine targeting Staphylococcus aureus . This study evaluated the efficacy and immunologic mechanisms of a vaccine containing a recombinant glycoprotein antigen (NDV-3) in mouse skin and skin structure infection (SSSI) due to methicillin-resistant S. aureus (MRSA). Compared with adjuvant alone, NDV-3 reduced abscess progression, severity, and MRSA density in skin, as well as hematogenous dissemination to kidney. NDV-3 induced increases in CD3+ T-cell and neutrophil infiltration and IL-17A, IL-22, and host defense peptide expression in local settings of SSSI abscesses. Vaccine induction of IL-22 was necessary for protective mitigation of cutaneous infection. By comparison, protection against hematogenous dissemination required the induction of IL-17A and IL-22 by NDV-3. These findings demonstrate that NDV-3 protective efficacy against MRSA in SSSI involves a robust and complementary response integrating innate and adaptive immune mechanisms. These results support further evaluation of the NDV-3 vaccine to address disease due to S. aureus in humans.