Kinetic and phenotypic analysis of CD8+ T cell responses after priming with alphavirus replicons and homologous or heterologous booster immunizations

J Virol. 2014; pii: JVI.02223-14.

Knudsen ML, Ljungberg K, Kakoulidou M, Kostic L, Hallengärd D, García-Arriaza J, Merits A, Esteban M, Liljeström P.

J Virol. 2014; pii: JVI.02223-14Alphavirus replicons are potent inducers of CD8+ T cell responses and thus constitute an attractive vaccine vector platform for developing novel vaccines. However, the kinetics and memory phenotype of CD8+ T cell responses induced by alphavirus replicons are not well characterized. Furthermore, little is known how priming with alphavirus replicons affects booster immune responses induced by other vaccine modalities. We demonstrate that a single immunization with an alphavirus replicon, administered as viral particles or naked DNA, induced an antigen-specific CD8+ T cell response that had a sharp peak, followed by a rapid contraction. Administering a homologous boost before contraction had occurred did not further increase the response. In contrast, boosting after contraction when CD8+ T cells had obtained a memory phenotype (based on CD127/CD62L expression), resulted in maintenance of CD8+ T cells with a high recall capacity (based on CD27/CD43 expression). Increasing the dose of replicon particles promoted T effector memory (Tem) and inhibited T central memory (Tcm) development. Moreover, infection with a replicating alphavirus induced a similar distribution of CD8+ T cells as the replicon vector. Lastly, the distribution of T cell subpopulations induced by a DNA-launched alphavirus replicon could be altered by heterologous boosts. For instance, boosting with a poxvirus vector (MVA) favored expansion of the Tem compartment. In summary, we have characterized the antigen-specific CD8+ T cell response induced by alphavirus replicon vectors and demonstrated how it can be altered by homologous and heterologous boost immunizations.

Importance Alphavirus replicons are promising vaccine candidates against a number of diseases and are by themselves developed as vaccines against for example chikungunya virus infection. Replicons are also considered to be used for priming followed by booster immunization using different vaccine modalities. In order to rationally design prime-boost immunization schedules with these vectors, characterization of the magnitude and phenotype of CD8+ T cell responses induced by alphavirus replicons is needed. Here, we demonstrate how factors such as timing and dose affect the phenotype of the memory T cell populations induced by immunization with alphavirus replicons. These findings are important for designing future clinical trials with alphaviruses, as they can be used to tailor vaccination regimens in order to induce a CD8+ T cell response that is optimal for control and/or clearance of a specific pathogen.

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