Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-05, Vol.108 (19), p.7914-7919
• Main Authors: MacLeod, Megan K.L, McKee, Amy S, David, Alexandria, Wang, Jieru, Mason, Robert, Kappler, John W, Marrack, Philippa
• Format: Article
• Language: English
• Subjects: Adjuvants; Adjuvants, Immunologic - administration & dosage; Alum Compounds - administration & dosage; Aluminum; Animals; Antibodies; Antigen Presentation; Antigens; Antigens, Surface - biosynthesis; Apoptosis Regulatory Proteins - biosynthesis; Biological Sciences; Cattle; CD8 antigen; CD8-positive T-lymphocytes; cell-mediated immunity; Cellular differentiation; Cytokines - biosynthesis; Cytotoxicity; Differentiation; Female; granzyme B; Humans; Immunization; Immunologic Memory; Immunological memory; Infection; Infections; Infectious diseases; Influenza; Influenza A; Influenza A virus; Influenza A virus - immunology; Interleukin 6; Interleukin-6 - biosynthesis; Interleukin-6 - deficiency; Interleukin-6 - genetics; lipid A; Lipid A - administration & dosage; Lipid A - analogs & derivatives; Lymphocytes T; Memory; Memory cells; Mice; Mice, Knockout; Mice, Transgenic; Molecules; Monophosphoryl lipid A; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - prevention & control; Ova; Ovalbumin - administration & dosage; Ovalbumin - immunology; Programmed Cell Death 1 Receptor; RNA-Binding Proteins - administration & dosage; RNA-Binding Proteins - immunology; Rodents; Salts; Serum Albumin, Bovine - administration & dosage; Serum Albumin, Bovine - immunology; T cell receptors; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; Vaccination; vaccine adjuvants; vaccine development; Vaccines; Vaccines, Subunit - administration & dosage; Viral Core Proteins - administration & dosage; Viral Core Proteins - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1104588108

Vaccines can greatly reduce the spread of and deaths from many infectious diseases. However, many infections have no successful vaccines. Better understanding of the generation of protective CD8 memory T cells by vaccination is essential for the rational design of new vaccines that aim to prime cellular immune responses. Here we demonstrate that the combination of two adjuvants that are currently licensed for use in humans can be used to prime long-lived memory CD8 T cells that protect mice from viral challenge. The universally used adjuvant, aluminum salts, primed long-lived memory CD8 T cells; however, effective cytotoxic T-cell differentiation occurred only in the presence of an additional adjuvant, monophosphoryl lipid A (MPL). MPL-induced IL-6 was required for cytotoxic differentiation. The IL-6 acted by inducing granzyme B production and reducing expression of inhibitory molecule PD1 on the surface of the primed CD8 T cells. CD8 memory T cells generated by antigen delivered with both aluminum salts and MPL provided significant protection from influenza A challenge. These adjuvants could be used in human vaccines to prime protective memory CD8 T cells.