Superior Protective Immunity against Murine Listeriosis by Combined Vaccination with CpG DNA and RecombinantSalmonella entericaSerovar Typhimurium

Abstract

Preexisting antivector immunity can severely compromise the ability of Salmonella enterica serovar Typhimurium live vaccines to induce protective CD8 T-cell frequencies after type III secretion system-mediated heterologous protein translocation in orally immunized mice. To circumvent this problem, we injected CpG DNA admixed to the immunodominant p60 217-225 peptide from Listeria monocytogenes subcutaneously into BALB/c mice and coadministered a p60-translocating Salmonella strain by the orogastric route. The distribution of tetramer-positive p60 217-225 -specific effector and memory CD8 T cells was analyzed by costaining of lymphocytes with CD62L and CD127. In contrast to the single oral application of recombinant Salmonella or single immunization with CpG and p60, in the spleens from mice immunized with a combination of both vaccine types a significantly higher level of p60-specific CD8 T cells with a predominance of the effector memory T-cell subset was detected. In vivo protection studies revealed that this CD8 T-cell population conferred sterile protective immunity against a lethal infection with L. monocytogenes. However, p60-specific central memory CD8 T cells induced by single vaccination with CpG and p60 were not able confer effective protection against rapidly replicating intracellular Listeria. In conclusion, we provide compelling evidence that the combination of Salmonella type III-mediated antigen delivery and CpG immunization is an attractive novel vaccination strategy to modulate CD8 differentiation patterns toward distinct antigen-specific T-cell subsets with favorable protective capacities.The type III secretion system (T3SS) of Salmonella enterica serovar Typhimurium can be used to target heterologous antigens directly into the cytosol of antigen-presenting cells (30,32,33). Our laboratory has reported that the single oral immunization of mice with a recombinant Salmonella strain expressing the translocated Yersinia outer protein E (YopE) fused to the immunodominant antigen p60 from Listeria monocytogenes results in the efficient induction of p60-specific CD8 T cells (33). In further experiments, we explored the possibility to induce enhanced levels of antigen-specific CD8 T cells by oral boost immunization using the same recombinant serovar Typhimurium strain (38). We demonstrated that the rapid clearance of the Salmonella vaccine carrier due to anti-Salmonella vector immunity after the second immunization prevents a significant elevation of T-lymphocyte numbers (38). In a more recent study, we showed that heterologous prime-boost immunizations using attenuated serovar Typhimurium and serovar Dublin strains for foreign antigen delivery can be used to bypass anti-Salmonella immunity resulting in enhanced antigen-specific CD8 T-cell induction (40). However, the translation of this heterologous prime-boost immunization approach from mice to man is not trivial due to the lack of S. enterica vaccine strains with different O antigens approved for use in humans.An alternative vaccination strategy to ...

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

“…As expected, no appreciable CD8 ϩ T cell response was detected after DENV PIV-1 vaccination. Vaccine-elicited CD8 ϩ T cell responses have particular requirements for priming, such as proinflammatory conditions that are provided only in the context of viral vector replication (45)(46)(47), the presence of viral nucleic acids (48,49), or specific adjuvants (50). These data therefore suggest that the T cell response induced by PIV-1 vaccination is limited to antigen-specific CD4 ϩ T helper cells which support the production of anti-DENV antibodies.…”

Assessment of the Phenotype and Functionality of Porcine CD8 T Cell Responses following Vaccination with Live Attenuated Classical Swine Fever Virus (CSFV) and Virulent CSFV Challenge

“…The data presented here suggest that CSFV-specific IFN-␥-expressing cells may also have cytotoxic capacity and consolidate our previous results where we showed that IFN-␥ expression was restricted to CD8 T cells expressing intracellular perforin (7) and other earlier studies that demonstrated CSFV-specific cytotoxic activity by T cell cultures isolated from vaccinated pigs (8)(9)(10). While IFN-␥-secreting T EM cells have been implicated in protection against a variety of intracellular pathogens, simultaneous production of IFN-␥, TNF-␣, and IL-2 detected at the single-cell level by multiparameter flow cytometry has been correlated with enhanced vaccine-induced protection (45)(46)(47)(48)(49)(50)(51). Moreover, data suggest that such polyfunctional CD8 T memory cells are critical to long-term protection against other viruses belonging to the family Flaviviridae (20,22).…”

CD8 T-Cell Induction against Vascular Endothelial Growth Factor Receptor 2 by Salmonella for Vaccination Purposes against a Murine Melanoma

“…However, proliferative capacity does not necessarily correlate with protection against infection, since T CMC -like CD8 T cells induced by vaccination with heat-killed L. monocytogenes reveal vigorous proliferation and expansion after challenge with live Listeria , but do not protect against listeriosis as determined by clearance of the bacteria [43]. These findings were supported by a recent study demonstrating that T EMC are more effective than T CMC in conferring protection in the murine Listeria infection model [41], [44]. As mentioned above, the analysis of the kinetics of KDR2-specific CD8 T cell subpopulation formation after SB824 (pHR584) vaccination revealed a clear trend towards the induction of both memory T cell subsets.…”