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Competition between CTL narrows the immune response induced by prime-boost vaccination protocols

Palmowski, Michael J., Choi, Ed Man-Lik, Hermans, Ian F., Gilbert, Sarah C., Chen, Ji-Li, Gileadi, Uzi, Salio, Mariolina, Van Pel, Aline, Man, Stephen ORCID:, Bonin, Eivor, Liljestrom, Peter, Dunbar, P. Rod and Cerundolo, Vincenzo 2002. Competition between CTL narrows the immune response induced by prime-boost vaccination protocols. The Journal of Immunology 168 (9) , pp. 4391-4398. 10.4049/jimmunol.168.9.4391

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Recombinant vaccines encoding strings of virus- or tumor-derived peptides and/or proteins are currently being designed for use against both cancer and infectious diseases. These vaccines aim to induce cytotoxic immune responses against several Ags simultaneously. We developed a novel tetramer-based technique, based on chimeric HLA A2/H-2Kb H chains, to directly monitor the CTL response to such vaccines in HLA-A2 transgenic mice. We found that priming and boosting with the same polyepitope construct induced immune responses that were dominated by CTL of a single specificity. When a mixture of viruses encoding single proteins was used to boost the polyepitope primed response, CTL of multiple specificities were simultaneously expanded to highly effective levels in vivo. In addition, we show that a preexisting response to one of the epitopes encoded within a polyepitope construct significantly impaired the ability of the vaccine to expand CTL of other specificities. Our findings define a novel vaccination strategy optimized for the induction of an effective polyvalent cytotoxic response. Recent advances in our ability to detect and isolate Ag-specific CTL (1, 2, 3, 4) have accelerated the development of new vaccines targeting both infectious disease and cancer. These vaccines aim to induce the expansion of CTL specific for virus- or tumor-derived peptides (CTL epitopes) bound to MHC class I molecules. It has become clear that some of the most successful vaccination protocols for inducing epitope-specific CTL are the heterologous prime-boost protocols, involving sequential injections of different vectors encoding the same recombinant Ag. These protocols focus the CTL response toward peptides within the recombinant Ag, which are the only CTL epitopes shared by the different agents (5). Recent results have demonstrated that priming with plasmid DNA and boosting with recombinant modified vaccinia Ankara (MVA)4 generate high levels of specific immunity (6, 7, 8, 9). To minimize the generation of virus or tumor Ag loss variants (10, 11, 12), it would be desirable to induce CTL responses against a broad range of different epitopes, preferably encoded by distinct proteins. This rationale has led to the generation of polyvalent vaccines encoding strings of CTL epitopes (polyepitope vaccines) and/or proteins. Due to the large number of well-characterized HLA-A2 binding tumor- and virus-derived peptides, polyepitope vaccines are often designed to include peptides that can be presented by A2 to responding CTL. The availability of mice transgenic for A2 has allowed some preclinical testing of the efficacy of these vaccines. Polyepitope vaccine constructs are capable of priming multiple CTL specificities in A2 transgenic mice (13, 14, 15, 16) and also of expanding single CTL specificities to high numbers in nonhuman primates (8, 17). However, evidence is lacking that polyepitope constructs are capable of expanding CTL of multiple different specificities to effective levels. Systematic comparison of the efficacy of different polyvalent vaccination strategies has also been hampered by the technical limitations of assays for directly monitoring CTL responses in A2 transgenic mice (18). We reasoned that the use of polyepitope vaccines in a prime-boost strategy might lead to dominant expansion of CTL with a narrow CTL repertoire, as a result of the preferential expansion of immunodominant CTL responses. The identity of the mechanisms responsible for the expansion of immunodominant CTL responses is the subject of ongoing debate. Recent results have demonstrated that high-affinity CTL are capable of down-modulating peptide-MHC complexes on APCs (19), providing a mechanism for the preferential expansion of high-affinity CTL during a secondary T cell response. To address our hypothesis, we developed a novel technique, based on the use of chimeric A2/H-2Kb (Kb) class I tetramers, for directly monitoring A2-restricted CTL responses in the blood of A2 transgenic mice. This technique has allowed us to accurately and rapidly monitor the frequency of CTL induced by prime-boost regimens using a polyepitope construct designed for clinical trial in melanoma patients. We compared protocols using a number of different vectors and correlated the frequency of CTL induced with their cytotoxic activity in vivo. The results suggest a new strategy for optimizing polyvalent CTL responses in human vaccine trials.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: American Association of Immunologists
ISSN: 0022-1767
Date of Acceptance: 20 February 2002
Last Modified: 15 Mar 2023 17:00

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