The Reduced Immunogenicity of Zoster Vaccines in CMV-Seropositive Older Adults Correlates with T Cell Imprinting

Background: Cytomegalovirus (CMV) infection and age impact immune responses to vaccines. The effect of sex remains controversial. We investigated the relationship between cytomegalovirus-seropositivity, age, and sex and the immunogenicity of the recombinant (RZV) and live (ZVL) zoster vaccines in adults ≥50 years of age. Methods: Varicella zoster virus (VZV) glycoprotein E (gE)-specific antibody, antibody avidity, and cell-mediated immunity (CMI) were measured pre-vaccination and at regular intervals over 5 years post-vaccination in 80 RZV and 79 ZVL recipients, including 91 cytomegalovirus-seropositive and 90 female participants. Results: Differences associated with CMV-seropositivity: lower VZV-gE-CMI in RZV recipients after the first dose of vaccine, but no differences after the 2nd dose; lower VZV-gE-specific antibody avidity in ZVL recipients; and more abundant Th1 and senescent T cells (Tsen) and less abundant regulatory (Treg) and tissue-resident memory T cells (Trm). Differences associated with older age: lower antibody responses in RZV recipients and lower Th1 cells. Differences associated with sex: none for immunogenicity of either vaccine. Differences associated with T cell subset abundance: higher Tsens and lower Tregs or Trms were associated with lower post-dose 1 VZV-gE-specific CMI in RZV recipients, and higher Th1s were associated with higher antibody concentrations. Conclusions: The correlation of CMV- and age-associated T cell subsets with the immunogenicity of ZVLs and RZVs suggests that T cell imprinting contributes to the effect of age and CMV on vaccine responses.