Adenovirus-Based Vaccine against Listeria monocytogenes: Extending the Concept of Invariant Chain Linkage

Abstract

The use of replication-deficient adenoviruses as vehicles for transfer of foreign genes offers many advantages in a vaccine setting, eliciting strong cellular immune responses involving both CD8+ and CD4+ T cells. Further improving the immunogenicity, tethering of the inserted target Ag to MHC class II–associated invariant chain (Ii) greatly enhances both the presentation of most target Ags, as well as overall protection against viral infection, such as lymphocytic choriomeningitis virus (LCMV). The present study extends this vaccination concept to include protection against intracellular bacteria, using Listeria monocytogenes as a model organism. Protection in C57BL/6 mice against recombinant L. monocytogenes expressing an immunodominant epitope of the LCMV glycoprotein (GP33) was greatly accelerated, augmented, and prolonged following vaccination with an adenoviral vaccine encoding GP linked to Ii compared with vaccination with the unlinked vaccine. Studies using knockout mice demonstrated that CD8+ T cells were largely responsible for this protection, which is mediated through perforin-dependent lysis of infected cells and IFN-γ production. Taking the concept a step further, vaccination of C57BL/6 (L. monocytogenes–resistant) and BALB/c (L. monocytogenes–susceptible) mice with adenoviral vectors encoding natural L. monocytogenes-derived soluble Ags (listeriolysin O and p60) revealed that tethering of these Ags to Ii markedly improved the vaccine-induced CD8+ T cell response to two of three epitopes studied. More importantly, Ii linkage accelerated and augmented vaccine-induced protection in both mouse strains and prolonged protection, in particular that induced by the weak Ag, p60, in L. monocytogenes–susceptible BALB/c mice.

Enhanced Vaccine-Induced CD8+ T Cell Responses to Malaria Antigen ME-TRAP by Fusion to MHC Class II Invariant Chain

“…But Mary Collins’ laboratory at University College London, UK, was (to our knowledge) the first to describe an unexpected, additional effect on CD8 + T cell induction, using immunization with a lentiviral vector expressing ovalbumin fused to Ii (Ii-OVA) [16]. Subsequently, five reports from the University of Copenhagen [17]–[21] have documented enhanced induction of CD8 + T cell responses by human adenovirus 5 (HAdV-5) and plasmid DNA vectors expressing Ii-fused antigens.…”

“…The reduction in viral titre after challenge with vaccinia virus expressing NS3 was enhanced in an IFN-γ-dependent manner [17]. More recently vaccination with HAdV-5 vector expressing the GP-Ii fusion was shown to protect mice from intracellular bacteria using a Listeria monocytogenes challenge model [21].…”

Listeriosis in animals, its public health significance (food-borne zoonosis) and advances in diagnosis and control: a comprehensive review

“…This concept has been utilized for development of vaccines against L. monocytogenes, wherein adenoviral vector encodes soluble antigens derived from L. monocytogenes, i.e. listeriolysin and p60 (Darji et al 2003;Jensen et al 2013). Apart from this, gas-filled microbubbles (MB) has also been successfully used as an antigen delivery system for L. monocytogenes in inducing specific effector CD8(C) T cell responses (Bioley et al 2013(Bioley et al , 2015.…”

Early life vaccination: Generation of adult-quality memory CD8+ T cells in infant mice using non-replicating adenoviral vectors

“…In addition to Ad-liGP, two more adenoconstructs encoding CD8+ T-cell epitopes from Yellow Fever virus (YFV): Ad-YF CME and Ad-YF NS3, were investigated in the context of early life vaccination. Notably, the efficiency of all vaccine induced responses were tested using several different challenge models, all known to reflect CD8+ T-cell mediated protection as validated in one or more earlier studies29303132333435. Overall, our results illustrate that, at least for murine CD8+ T cells, there appear to be no major intrinsic functional deficiency, and that given optimal activating conditions efficient CD8+ T-cell-mediated immunity may be elicited in infants.…”