Heightened innate immune state induced by viral vector leads to enhanced response to challenge and prolongs malaria vaccine protection
Komi Gbedande,
Samad A. Ibitokou,
Mark Joseph D. Endrino,
George S. Yap,
Michael G. Brown,
Robin Stephens
Affiliations
Komi Gbedande
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA; Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA; Corresponding author
Samad A. Ibitokou
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
Mark Joseph D. Endrino
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
George S. Yap
Center for Immunity and Inflammation, and Department of Medicine, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
Michael G. Brown
Department of Medicine, Division of Nephrology, and the Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA
Robin Stephens
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA; Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Corresponding author
Summary: Cytomegalovirus is a promising vaccine vector; however, mechanisms promoting CD4 T cell responses to challenge, by CMV as a vector, are unknown. The ability of MCMV to prolong immunity generated by short-lived malaria vaccine was tested. MCMV provided non-specific protection to challenge with Plasmodium and increased interleukin-12 (IL-12) and CD8α+ dendritic cell (DC) numbers through prolonged MCMV-dependent interferon gamma (IFN-γ) production. This late innate response to MCMV increased IL-12 upon challenge and increased the polyclonal CD4 effector T cell response to Plasmodium, protecting in an IL-12-dependent manner. Although Plasmodium-vaccine-induced protection decayed by d200, MCMV restored protection through IFN-γ. Mechanistically, protection depended on MCMV-induced-IFN-γ increasing CD8α+ DCs and IL-12p40. MCMV expressing a Plasmodium epitope increased parasite-specific CD4 effector and effector memory T cells persisting after malaria vaccination, both phenotypes reported to protect. Overall, enhanced innate cell status, a mechanism of heterologous protection by MCMV, led to a stronger T cell response to challenge.
