Differential effect of Recombinant Zoster Vaccine (RZV) and Zoster Vaccine Live (ZVL) in a controlled human infection model (CHIM) of VZV reactivation 2307815

Abstract Introduction HZ results from uncontrolled VZV reactivation. Both ZVL and RZV protect against HZ, with RZV (AS01B-adjuvanted gE glycoprotein) showing higher efficacy. To investigate mechanisms underlying this difference, we developed a CHIM mimicking VZV reactivation. Methods A live VZV challenge (intradermal ZVL) was given to 105 adults ≥50 years immunized with ZVL or RZV 6-12 months (Recent) or ≥ 5 years (Remote) prior. We profiled virologic, transcriptional and immunologic responses in skin and blood on Days 0, 1, 3 and 7 post-challenge. Results Presence of VZV mRNA in all D1 skin biopsies and of VZV DNA in 74% D1 blood samples indicated ongoing viral replication that tapered through D7. D3 DNAemia was more common in Remote than Recent vaccinees, consistent with waning immunity. Plasma cytokines increased on D1 in all groups with higher D3-D7 levels in the Remote ZVL. Blood immune cell profiling showed higher D1 CD8+CTL and D3 CD4+CTL in Recent RZV, and higher D7 T cell proliferation in Remote ZVL. Higher CD4+CTL on D1 correlated with lower incidence of DNAemia on D3 indicating control of viral replication. Local responses included transcriptome changes from D1 in both groups; broader and more persistent cytokine induction in ZVL than RZV from D1; and D1 CD8+CTL and Teff expansion in RZV and D3-D7 innate and T cell expansion in ZVL. Overall, ZVL had delayed T cell and higher inflammatory responses than RZV. TRB sequence matching of VZV- and gE-specific cells derived from blood with D3 skin and D0 total blood showed higher total VZV-specific T cell clonotypes in skin and higher CD4+ and CD8+ gE-specific clonotypes in skin and blood in RZV than ZVL. Conclusion The CHIM effectively reproduced VZV reactivation. Early robust CD4+CTL responses in blood correlated with protection against VZV replication. Higher abundance of gE-specific T cells in blood, faster mobilization to the site of VZV infection, and lower local inflammation conferred by RZV than ZVL vaccination may explain its superior protective effect. Funding Source 1U01AI141919-01; 2U01AI141919-06 (NIAID) Topic Categories Vaccines and Immunotherapy (VAC)