title: Optimizing Immunization Strategies for the Induction of Antigen-Specific CD4 and CD8 T Cell Responses for Protection against Intracellular Parasites.
abstract: Immunization strategies that generate either CD4 or CD8 T cell responses are relatively well described, but less is known with regard to optimizing regimens to induce both CD4 and CD8 memory T cells. Considering the importance of both CD4 and CD8 T cells in the control of intracellular pathogens such as Leishmania donovani, we wanted to identify vaccines that could raise both CD4 and CD8 T cell responses and determine how to configure immunization strategies to generate the best combined protective T cell response. We examined responses generated against the Leishmania vaccine antigen F3 following its administration in either recombinant form with the Toll-like receptor 4 (TLR4) agonist-containing adjuvant formulation GLA-SE (F3+GLA-SE) or as a gene product delivered in an adenoviral vector (Ad5-F3). Homologous immunization strategies using only F3+GLA-SE or Ad5-F3 preferentially generated either CD4 or CD8 T cells, respectively. In contrast, heterologous strategies generated both antigen-specific CD4 and CD8 T cells. Administration of F3+GLA-SE before Ad5-F3 generated the greatest combined CD4 and CD8 responses. Cytotoxic CD8 T cell responses were highest when Th1 cells were generated prior to their induction by Ad5-F3. Finally, a single immunization with a combination of F3+GLA-SE mixed with Ad5-F3 was found to be sufficient to provide protection against experimental L. donovani infection. Taken together, our data delineate immunization regimens that induce antigen-specific CD4 and CD8 T cell memory responses, and identify a single immunization strategy that could be used to rapidly provide protection against intracellular pathogens in regions where access to health care is limited or sporadic.
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hofmeyer
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA mduthie@idri.org.
authors.forename: Malcolm S
authors.initials: MS
authors.lastname: Duthie
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Laurance
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Favila
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Van Hoeven
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007893:Leishmania donovani / Q000276:immunology*; D007896:Leishmaniasis / Q000517:prevention & control*; D054332:Leishmaniasis Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D054332:Leishmaniasis Vaccines; D014614:Vaccines, Synthetic