Expansion of the HSV-2–specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine
Emily S. Ford, Alvason Z. Li, Kerry J. Laing, Lichun Dong, Kurt Diem, Lichen Jing, Koshlan Mayer-Blackwell, Krithi Basu, Mariliis Ott, Jim Tartaglia, Sanjay Gurunathan, Jack L. Reid, Matyas Ecsedi, Aude G. Chapuis, Meei-Li Huang, Amalia S. Magaret, Christine Johnston, Jia Zhu, David M. Koelle, Lawrence Corey
Emily S. Ford, Alvason Z. Li, Kerry J. Laing, Lichun Dong, Kurt Diem, Lichen Jing, Koshlan Mayer-Blackwell, Krithi Basu, Mariliis Ott, Jim Tartaglia, Sanjay Gurunathan, Jack L. Reid, Matyas Ecsedi, Aude G. Chapuis, Meei-Li Huang, Amalia S. Magaret, Christine Johnston, Jia Zhu, David M. Koelle, Lawrence Corey
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Research Article Vaccines Virology

Expansion of the HSV-2–specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine

Abstract

The skin at the site of HSV-2 reactivation is enriched for HSV-2–specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells, we studied skin biopsies and HSV-2–reactive CD4+ T cells from PBMCs by T cell receptor (TCR) β chain (TRB) sequencing before and after vaccination with a replication-incompetent whole-virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2–reactive CD4+ TRB sequences from PBMCs in the skin TRB repertoire increased after the first vaccine dose. We found sustained expansion after vaccination of unique, skin-based T cell clonotypes that were not detected in HSV-2–reactive CD4+ T cells isolated from PBMCs. In one participant, a switch in immunodominance occurred with the emergence of a TCR αβ pair after vaccination that was not detected in blood. This TCRαβ was shown to be HSV-2 reactive by expression of a synthetic TCR in a Jurkat-based NR4A1 reporter system. The skin in areas of HSV-2 reactivation possessed an oligoclonal TRB repertoire that was distinct from the circulation. Defining the influence of therapeutic vaccination on the HSV-2–specific TRB repertoire requires tissue-based evaluation.

Authors

Emily S. Ford, Alvason Z. Li, Kerry J. Laing, Lichun Dong, Kurt Diem, Lichen Jing, Koshlan Mayer-Blackwell, Krithi Basu, Mariliis Ott, Jim Tartaglia, Sanjay Gurunathan, Jack L. Reid, Matyas Ecsedi, Aude G. Chapuis, Meei-Li Huang, Amalia S. Magaret, Christine Johnston, Jia Zhu, David M. Koelle, Lawrence Corey

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Figure 3

Prevalent and elicited clonotypes in HSV-2–enriched CD4+ T cells from PBMCs, healed lesion site, and arm biopsy expanding or detected at high copy number.

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Prevalent and elicited clonotypes in HSV-2–enriched CD4+ T cells from PB...
(A) Prevalent clonotypes detected in P4, by fold increase over dose 1. Each row represents a single clonotype (by nucleic acid sequence). Codetection of clonotypes in HSV-2–enriched CD4+ T cells from PBMCs, active lesion, quiescent lesion-area skin, and arm skin are compared at each of the time points. The number of copies detected in PBMCs from P4 at day 10 reflects ex vivo expansion prior to sequencing and is denoted in individual cells (see Methods). Blank boxes indicate lack of detection. (B) Prevalent and (C) elicited clonotypes either expanding ≥6-fold after dose 1 or present after dose 1 (day 10) at ≥6-fold above a single copy and their longevity in lesion-area tissue over the course of the vaccine trial (left), with the corresponding abundance in the arm control (right). ND, not detected. Highly prevalent clonotypes that expanded after the first vaccine dose are seen to persist in tissue throughout the vaccine trial. Color indicates whether the nucleotide sequences were detected in blood (black indicates a tissue-only sequence, red was also seen in blood). Prevalent expanded clonotypes are of greater abundance than elicited clonotypes. Most in-tissue expansion was not from clonotypes observed in blood. (D) Stacked bar graphs showing number of clonotypes expanding by ≥6-fold after each dose in the lesion-area skin by person. (E) Number of clonotypes expanding by ≥6-fold after each dose in the lesion-area skin by detection prior to initiation of vaccine series (prevalent) versus clonotypes only seen after initiation of vaccination (elicited). *P < 0.05 by Wilcoxon’s signed-rank test.