A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens

Author:

Yan Jun1ORCID,Nielsen Travis B.12ORCID,Lu Peggy1ORCID,Talyansky Yuli1ORCID,Slarve Matt1,Reza Hernan1ORCID,Novakovic Boris3ORCID,Netea Mihai G.45,Keller Ashley E.6ORCID,Warren Troy6,DiGiandomenico Antonio6ORCID,Sellman Bret R.6ORCID,Luna Brian M.1ORCID,Spellberg Brad7

Affiliation:

1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

2. UC San Diego School of Medicine, University of California San Diego, San Diego, CA 92093, USA.

3. Murdoch Children’s Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, VIC 3052, Australia.

4. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.

5. Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.

6. AstraZeneca Inc., Early Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.

7. Los Angeles General Medical Center, Los Angeles, CA 90033, USA.

Abstract

Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care–associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus , vancomycin-resistant Enterococcus faecalis , extended-spectrum beta-lactamase–expressing Escherichia coli , and carbapenem-resistant strains of Acinetobacter baumannii , Klebsiella pneumoniae , and Pseudomonas aeruginosa. The vaccine also conferred protection against the fungi Rhizopus delemar and Candida albicans . Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care–associated infections.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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