Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Chronically Immunosuppressed Adults Following Renal Transplant: A Phase 3, Randomized Clinical Trial

Abstract

Background: The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy.

Methods: In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1-2 months (M) apart 4-18M posttransplant. Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2.

Results: Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post-dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups.

Conclusions: RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose.

Clinical trials registration: NCT02058589.

Keywords: herpes zoster vaccine; immunogenicity; immunosuppression; renal transplant; safety.

Figure 1.

Participant flowchart. Abbreviations: AE, adverse event; ATP, according to protocol; CMI, cell-mediated immunogenicity; M, study month; n, number of participants in each category; pIMD, potential immune-mediated disease; Placebo, participants receiving placebo; RZV, participants receiving the recombinant adjuvanted herpes zoster vaccine; SAE, serious adverse event; TVC, total vaccinated cohort.

Figure 2.

Humoral immune responses (according-to-protocol cohort for humoral immunogenicity). A, Anti-gE antibody geometric mean concentration; B, humoral vaccine response rate. Vaccine response rate in terms of anti–glycoprotein E (gE) humoral response was defined as the percentage of participants with postvaccination anti-gE concentrations (i) ≥4-fold the technical cutoff of assay quantification (for initially seronegative participants) or (ii) ≥4-fold the prevaccination concentration (for initially seropositive participants). Abbreviations: GMC, geometric mean concentration; M, study month; N, number of participants in the according-to-protocol cohort for humoral immunogenicity; Placebo, participants receiving placebo; RZV, participants receiving the recombinant adjuvanted herpes zoster vaccine; VRR, vaccine response rate.

Figure 3.

Cell-mediated immune responses (according-to-protocol cohort for cell-mediated immunogenicity). A, CD4[2+] T-cell frequencies; B, cell-mediated vaccine response rate. Vaccine response rate in terms of CD4[2+] T-cell response was defined as the percentage of participants with postvaccination CD4[2+] T-cell frequencies (i) ≥2-fold the cutoff (320 positive cells per 10⁶ CD4 ⁺ T cells counted) (for participants initially below the cutoff) or (ii) ≥2-fold the prevaccination CD4[2+] T-cell frequencies (for participants initially above the cutoff). Abbreviations: CD4[2+], CD4 ⁺ T cells expressing at least 2 activation markers of the 4 markers assessed (interferon-γ, interleukin 2, tumor necrosis factor–α, and CD40 ligand); CMI, cell-mediated immunogenicity; M, study month; N, number of participants in the according-to-protocol cohort for cell-mediated immunogenicity; Placebo, participants receiving placebo; RZV, participants receiving the recombinant adjuvanted herpes zoster vaccine; VRR, vaccine response rate.

Figure 4.

Reactogenicity in the total vaccinated cohort. Error bars indicate 95% confidence intervals. Fever was defined as body temperature ≥37.5°C. Abbreviations: GI, gastrointestinal symptoms (nausea, vomiting, diarrhea, and/or abdominal pain); N, number of participants with at least 1 documented vaccine administration; Placebo, participants receiving placebo; RZV, participants receiving the recombinant adjuvanted herpes zoster vaccine. *Fever was not graded in this study. For fever, body temperatures >39°C are presented as grade 3.

Figure 5.

“Focus on the patient” section.