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.

A Canine-Directed Chimeric Multi-Epitope Vaccine Induced Protective Immune Responses in BALB/c Mice Infected with Leishmania infantum

“…An assessment of T cells phenotype after vaccination revealed that LiChimera/Addavax-vaccinated mouse group presented increased numbers of antigen-specific multifunctional IFN-γ + TNFα + IL-2 + CD4 + and CD8 + T cells as compared with the untreated controls. Recent studies have shown that the vaccine-induced generation of both CD4 + and CD8 + T multifunctional cells was a marker of vaccine efficacy against intracellular pathogens, such as Leishmania [ 78 , 79 , 80 , 81 , 82 , 83 ]. However, the frequency of double-positive IFN-γ + TNFα + , as well as single-positive IFN-γ + CD4 + T cells was higher than that of triple-positive cells.…”

Vaccines for Human Leishmaniasis: Where Do We Stand and What Is Still Missing?

“…coding for de facto effective antigens such as KMP-11, LACK, Leish-F3 and HASPB, were tested in the pre-clinical context for both CL and VL, with promising results obtained in all animal models used (mice, dogs and macaques) [51,84,[120][121][122][123]. Remarkably, one of them was the first third-generation anti-Leishmania vaccine candidate to undergo human clinical trials.…”

Not All Antigens Are Created Equally: Progress, Challenges, and Lessons Associated with Developing a Vaccine for Leishmaniasis

“…Using a variety of prime boost schemes involving Ad5-A2 as well as recombinant protein and a plasmid DNA-encoding A2 gene (DNA-A2), parasite burdens in the liver were lower in immunized macaques and correlated with hepatic granuloma resolution and the reduction of clinical symptoms. Considering the importance of both CD4 and CD8 T cells in the control of Leishmania infection, we recently generated an adenoviral vector expressing the F3 protein (Ad5-F3) to complement the use of recombinant F3 and investigated immunization strategies with the promise of generating combined protective T-cell responses (40). Overall, a F3ϩGLA-SE prime/Ad5-F3 boost strategy induced the best combined CD4 and CD8 T cell memory response, although we also found that simultaneous immunization with Ad5-F3 and F3ϩGLA-SE in a single injection was potent enough to provide protection.…”