Recruitment of naive CD4(+) T cells by the recombinant zoster vaccine correlates with persistent immunity

Herpes zoster (HZ) is a substantial problem for people with decreased cell-mediated immunity, including older adults. The first vaccine approved for HZ prevention, the zoster vaccine live (ZVL), which provided limited and short-lived protection, has been supplanted by the superior recombinant zoster vaccine (RZV), which provides robust and durable protection. To understand the mechanisms underlying the differential immunologic characteristics of the 2 vaccines, we used T cell receptor β chain sequencing and peptide–MHC class II tetramer staining to analyze recombinant glycoprotein E–specific (gE-specific) CD4(+) T cell clonotypes in RZV and ZVL recipients. Compared with ZVL, RZV expanded more gE-specific CD4(+) clonotypes, with greater breadth and higher frequency of public clonotypes. RZV recruited a higher proportion of clonotypes from naive than from memory cells, while ZVL recruited equally from memory and naive compartments. Compared with memory-derived, naive-derived clonotypes were more likely to last 5 or more years after immunization. Moreover, the frequency of tetramer(+) persistent clones correlated with the frequency of tetramer(+) naive CD4(+) prevaccination T cells. We conclude that the ability of RZV to recruit naive CD4(+) T cells into the response may contribute to the durability of its effect. The abundance, breadth, and frequency of public clonotypes may further add to its protective effect.