Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens

Abstract

An important focus in vaccine research is the design of vaccine vectors with low seroprevalence and high immunogenicity. Replication-incompetent lymphocytic choriomeningitis virus (rLCMV) vectors do not elicit vector-neutralizing antibody responses, and homologous prime-boost regimens with rLCMV vectors induce boostable and protective T cell responses to model antigens in mice. However, cellular and humoral immune responses following homologous rLCMV vaccine regimens have not been rigorously evaluated in non-human primates (NHPs). To test whether rLCMV vectors constitute an effective vaccine platform in NHPs, we developed rLCMV vectors expressing SIVmac239 Env and Gag antigens and assessed their immunogenicity in mice and cynomolgus macaques. Immunization with rLCMV vaccine vectors expressing SIV Env and Gag was effective at generating SIV-specific T cell and antibody responses in both mice and NHPs. Epitope mapping using SIV Env in C57BL/6 mice demonstrated that rLCMV vectors induced sustained poly-functional responses to both dominant and subdominant epitopes. Our results suggest the potential of rLCMV vectors as vaccine candidates. Future SIV challenge experiments in rhesus macaques will be needed to assess immune protection by these vaccine vectors.

T regulatory cells are critical for the maintenance, anamnestic expansion and protection elicited by vaccine‐induced CD8 T cells

“…Second, we generalize our observations to a prime‐boost vaccination setting using replication‐defective SIV vaccines that we have pre‐clinically tested in non‐human primates as candidate HIV vaccines . We show in a prime‐boost immunization regimen that Treg cells are also needed to generate effective vaccine‐induced CD8 T‐cell responses that can undergo robust recall expansion following vaccine boosting.…”

“…a), which is known to induce a chronic infection in unvaccinated mice . Vaccination with replication‐incompetent rCl‐13 vectors followed by replicating LCMV Cl‐13 challenge is a model that we have developed to assess vaccine‐induced protection in mice . We measured viral loads after challenge by plaque assays, and this showed a 12‐fold higher viraemia at day 6 in mice that were transiently Treg‐depleted after rCl‐13 vaccination ( P = 0·008), but at day 15 post‐challenge, all vaccinated mice had cleared the infection (Fig.…”

“…For acutely controlled viral challenges, lymphocytic choriomeningitis virus (LCMV) Armstrong was injected intraperitoneally at 2 × 10 5 plaque‐forming units per mouse. For modelling a vaccination regimen, mice were immunized intramuscularly with 10 5 focus‐forming units of replication incompetent LCMV Cl‐l3 vectors (rCl‐13) expressing simian immunodeficiency virus (SIV) strain SIVmac239 Env and Gag, as shown previously . For viral challenges, chronic LCMV Cl‐13 was injected intravenously via the lateral tail vein at 2 × 10 6 plaque‐forming units per mouse.…”

Novel Concepts for HIV Vaccine Vector Design

“…Although heterologous prime-boost vaccine regimens are often used to overcome this challenge, a single vector not hampered by preexisting humoral immunity is preferable, as it simplifies the prime-boost vaccine regimen and reduces the cost of production. To achieve this, a vector based on the arenavirus LCMV (which has been a main workhorse in basic immunology research because of its potent immunogenicity) was recently developed ( 79 , 80 ). LCMV is a bisegmented negative-strand RNA virus that primarily infects rodents and has been widely used as a model to study cellular immunity ( 81 , 82 ).…”

“…The genetic absence of the GP gene in rLCMV vectors renders the virus replication defective, overriding concerns about potential LCMV-induced pathogenicity, which are especially considered in pregnant women and transplant recipients ( 84 , 85 ). Interestingly, consecutive readministration of this vector as a homologous boost can lead to substantial anamnestic expansion of transgene-specific CD8 T cells and antibody responses without generating LCMV GP-specific neutralizing antibody responses ( 79 , 80 ). Therefore, rLCMV provides an option for simpler, immunogenic homologous prime-boost vaccine modalities.…”