Abstract
Attenuated vaccinia virus (VACV) vectors are considered prime vaccine candidates for use in immunotherapy of infectious disease. In spite of this, recent data show that the level of attenuation may hamper the efficient generation of protective CD8 T cells. This suggests that additional adjuvant-like activities may need to be combined with attenuated VACV for optimal vaccination. Stimulatory reagents to the TNFR family molecule 4-1BB (CD137) may represent such an adjuvant for vaccination. Previous murine studies have found that 4-1BB can participate in optimal priming of effector and memory CD8 T cells in response to several virus infections, and concordantly direct stimulation of 4-1BB with agonist reagents effectively boosts the CD8 T cell response against those viruses. In contrast, we recently reported that 4-1BB plays no role in the response to a virulent strain of VACV, questioning whether agonists of 4-1BB will be useful adjuvants for vaccination with VACV vectors. Here we show that agonist anti-4-1BB strongly enhanced the primary viral-specific effector CD8 T cell response during infection with live virulent VACV and attenuated VACV, and during immunization with VACV peptides given in IFA. However, accumulation of memory CD8 T cells was enhanced only following infection with virulent VACV or with peptide vaccination, but not with attenuated VACV, correlating in part with more transient expression of 4-1BB on CD8 T cells with attenuated virus. Our data therefore suggest that 4-1BB may be a promising candidate for targeting as an adjuvant for short-term enhancement of CD8 T cell responses with VACV vaccine strategies, but additional receptors may need to be engaged with 4-1BB to allow long-term CD8 T cell immunity with attenuated VACV vectors.
Highlights
A challenge for the development of vaccines and vectors for immunotherapy of infectious disease is to allow safe delivery of T cell epitopes that will induce efficient short or long-term cell-mediated immune responses
We previously found that endogenous 4-1BB/4-1BBL interactions played no apparent role in driving the CD8 T cell response following an infection with the vaccinia viruses (VACV)-WR (Zhao and Croft, 2012)
Here, we show that treatment of mice with an agonist antibody to 4-1BB strongly promotes the expansion and accumulation of virus-specific primary effector CD8 T cells during infection with live virulent and attenuated VACV or with an immunization strategy with VACV peptides
Summary
A challenge for the development of vaccines and vectors for immunotherapy of infectious disease is to allow safe delivery of T cell epitopes that will induce efficient short or long-term cell-mediated immune responses. While many researchers might acknowledge that live vaccines or viral vectors are the best way to induce cell-mediated immunity and CD8 T cell responses, there is concern about the safety of live vaccines and in particular about adverse side effects that might result with viruses or viral vectors that replicate strongly and spread within the host. In this regard, the study of vaccinia viruses (VACV) is of relevance as they are considered to be prime candidates for use in immunotherapy. Poor viral replication will translate into poor induction of T cell immunity
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