Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity

Abstract

Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8+ T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.

Induction of CD8 T Cell Heterologous Protection by a Single Dose of Single-Cycle Infectious Influenza Virus

“…By removing the ability of a virus to spread after initial infection, bona fide immune stimulation could be elicited without causing the pathogenesis that is associated with nascent virus production. This method has been used for developing several single-cycle replicating viruses, such as herpes simplex virus, simian immunodeficiency virus, West Nile virus, rabies virus, lymphocytic choriomeningitis virus, and murine cytomegalovirus (11)(12)(13)(14)(15)(16). One advantage of the single-cycle replicating virus is that it can trigger effective CD8 T cell responses (14,16,17).…”

Immunization with Biodegradable Nanoparticles Efficiently Induces Cellular Immunity and Protects against Influenza Virus Infection

“…Furthermore, an inactivated vaccine is insufficient protection against antigenic drift variants and does not provide protection against viruses from different subtypes. To this end, engineered live vaccine vectors, such as nonreplicating recombinant viruses expressing viral Ags, have been developed; these vectors induce the expansion of virus-specific T cells in murine models (3)(4)(5). Although these approaches have generated successful results, antivector immunity and safety concerns associated with live vectors complicate the development of live-vector vaccines (3).…”

Harnessing the Potential of Adenovirus Vectored Vaccines

“…administration is not likely to be due to differences in antigen as Flatz et al (Flatz et al, 2010) also noted a profound attenuation of the response after intravenously administration of 2.5x10 8 pfu of adenovirus encoding the SIINFEKL containing ovalbumin sequence, whereas a potent response was observed at lower doses, all measured at 28 days post vaccination. Thus, whereas the difference between our report and the one of Flatz et al (Flatz et al, 2010), who observed a strong response to low doses of ovalbumin encoding adenovirus, are likely due to the immunological potency of the encoded antigen (ovalbumin being a potent antigen, while β-galactosidase is a weak antigen), the differences between Flatz and Bramson must relate to the route of administration. In this regard it is interesting that we observed an early, transient cytokine competent CD8+ T cell response in the liver following i.v.…”

“…The most likely explanation for this phenomenon is that the early transgene-specific T cell response is aborted within the liver parenchyma as previously reported for the adenovirus-specific response following i.v. immunization (Liu et al, 2001), and that systemic T-cell expansion can only occur after a reduction in transgene expression in the liver or when a lower inoculum has been used to induce the response as seen by Flatz et al (Flatz et al, 2010). Based on our findings that peripheral virus administration leads to a marked increase in hepatic transduction when the dose is increased from 10 9 to 10 10 particles, and that the entire increase in dose at 10 11 particles enters the systemic circulation, we would think that working with peripheral administration of adenovirus at doses above 10 9 particles in murine systems entails a major risk for variability in response magnitude, kinetics and quality.…”