Recombinant LCMV Vectors Induce Protective Immunity following Homologous and Heterologous Vaccinations

Abstract

Successful vaccination against cancer and infectious diseases relies on the induction of adaptive immune responses that induce high-titer antibodies or potent cytoxic T cell responses. In contrast to humoral vaccines, the amplification of cellular immune responses is often hampered by anti-vector immunity that either pre-exists or develops after repeated homologous vaccination. Replication-defective lymphocytic choriomeningitis virus (LCMV) vectors represent a novel generation of vaccination vectors that induce potent immune responses while escaping recognition by neutralizing antibodies. Here, we characterize the CD8 T cell immune response induced by replication-defective recombinant LCMV (rLCMV) vectors with regard to expansion kinetics, trafficking, phenotype, and function and we perform head-to-head comparisons of the novel rLCMV vectors with established vectors derived from adenovirus, vaccinia virus, or Listeria monocytogenes. Our results demonstrate that replication-deficient rLCMV vectors are safe and ideally suited for both homologous and heterologous vaccination regimens to achieve optimal amplification of CD8 T cell immune responses in vivo.

Combination immunotherapy with two attenuated Listeria strains carrying shuffled HPV-16 E6E7 protein causes tumor regression in a mouse tumor model

“…Moreover, all of the previous studies on Listeria -based therapeutic vaccines utilized only LM as an antigen delivery carrier, and in nearly all reports, the same LM-based vaccine was applied repeatedly; that is homologous prime-boost immunization was performed. One drawback of homologous prime-boost immunization is that may result in anti-vector immunity, leading to early bacterial clearance, loss of gene expression and limitation of amplification of cellular immune responses 15 . To attempt to overcome this anti-vector immunity, we innovatively utilized both attenuated LM and LI strains in which the two virulence genes actA and plcB were knocked out to deliver the fused HPV-16 E6E7 antigen protein.…”

Advances in Development and Application of Influenza Vaccines

“…Previous studies have demonstrated that arenaviruses mainly infect important immune cells, such as dendritic cells (DCs) and macrophages, at the early stage of infection, which make them an ideal viral vector for vaccine development as they target these antigen-presenting cells (APCs) that can naturally enhance immune responses against the antigenic proteins ( 125 , 126 ). Several studies have utilized reverse genetics technology to generate recombinant LCMV carrying antigenic proteins of interest ( 127 , 128 ). Emonet and colleagues ( 129 ) developed a three-plasmid reverse genetics system to generate a tri-segmented LCMV.…”

Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity

“…Given the challenges associated with identifying CD4 T cell peptides presented following antigen exposure, coupled with the significant resources required to develop and validate a TCR transgenic, most studies have instead leveraged existing tools designed to evaluate the immune response to a model antigen by incorporating the antigen into the overall immunogen studied. This approach has been used for decades to study the immune response to viruses, bacteria, transplanted tissue and transfusion of blood products [ 60 , 65 , 66 , 67 , 68 ]. In each setting, despite the similar nature of the antigen targeted, the observed immune response appears to largely be governed by the vehicle containing the model antigen [ 60 , 65 , 66 , 67 , 68 ].…”

“…This approach has been used for decades to study the immune response to viruses, bacteria, transplanted tissue and transfusion of blood products [ 60 , 65 , 66 , 67 , 68 ]. In each setting, despite the similar nature of the antigen targeted, the observed immune response appears to largely be governed by the vehicle containing the model antigen [ 60 , 65 , 66 , 67 , 68 ]. However, while this strategy has been employed in a variety of settings and has provided important insight into immunology in general, similar strategies have not been employed to define the CD4 T cell response to protein-based drug therapies.…”