Abstract
Abstract 1394
Herpes zoster incidence is higher in patients undergoing chemotherapy for hematologic malignancy [HM] (25-100 cases/1000 person-years) than in the general population (≂f3-5 cases/1000 person-years) and the general older adult population (7-12 cases/1000 person-years). The licensed live-attenuated zoster vaccine was heat-treated [ZVHT] and assessed in adults with HM.
Randomized, double-blind, placebo-controlled, multicenter Phase I study of 4 ZVHT doses (≂f30 days apart) in adults ≥18 years with HM. Eighty subjects were enrolled, of whom 61 received ZVHT and 19 placebo (Pbo). Blood was collected at baseline and ≂f28 days after each dose to measure (1) VZV antibody concentrations by glycoprotein enzyme-linked immunosorbent assay (gpELISA), and (2) varicella zoster virus (VZV) T-cell responses by interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT) assay. All vaccinated patients were evaluated for adverse events (AEs) through day 28 postdose 4.
The primary hypothesis was that 4 doses of ZVHT would elicit a statistically significant VZV-specific immune response (lower bound of 90% CI on geometric mean fold rise [GMFR] >1.0) in adults with HM.
Injection-site adverse events (AEs) occurred in 31.1% of the ZVHT group and 10.5% of the Pbo group. Of overall vaccine-related systemic AEs (ZVHT: 18.0%, Pbo: 15.8%), only nausea was reported by >10% in either group (ZVHT: 0.0%, Pbo: 10.5%). There were 2 reported vaccine-related serious AEs in the ZVHT group (vomiting, 2 days postdose 1; peripheral neuropathy, 6 days postdose 2). Four AEs resulting in death were reported in the ZVHT group (coronary arteriosclerosis, 24 days postdose 1; malignant neoplasm, 18 days postdose 2; leukemia, 10 days postdose 2; neutropenic sepsis, 48 days postdose 2), all deemed not vaccine-related by the investigator. Two subjects discontinued due to vaccine-related AEs (peripheral neuropathy, ZVHT 6 days postdose 2; nausea and vomiting, Pbo 2 days postdose 1). No ZVHT recipient had a rash that was PCR positive for the vaccine strain of VZV.
Adverse Event Summary
| . | ZVHT Group (N=61) . | Placebo Group (N=19) . | ||
|---|---|---|---|---|
| n . | (%) . | n . | (%) . | |
| With one or more AE | 53 | (86.9) | 10 | (52.6) |
| With vaccine-related AEs† | 24 | (39.3) | 5 | (26.3) |
| Injection-site AEs† | 19 | (31.1) | 2 | (10.5) |
| Systemic AEs† | 11 | (18.0) | 3 | (15.8) |
| With serious AEs | 12 | (19.7) | 1 | (5.3) |
| Serious vaccine-related AEs | 2 | (3.3) | 0 | (0.0) |
| Who died | 4 | (6.6) | 0 | (0.0) |
| Discontinued due to a vaccine-related AE | 1 | (1.6) | 1 | (5.3) |
| . | ZVHT Group (N=61) . | Placebo Group (N=19) . | ||
|---|---|---|---|---|
| n . | (%) . | n . | (%) . | |
| With one or more AE | 53 | (86.9) | 10 | (52.6) |
| With vaccine-related AEs† | 24 | (39.3) | 5 | (26.3) |
| Injection-site AEs† | 19 | (31.1) | 2 | (10.5) |
| Systemic AEs† | 11 | (18.0) | 3 | (15.8) |
| With serious AEs | 12 | (19.7) | 1 | (5.3) |
| Serious vaccine-related AEs | 2 | (3.3) | 0 | (0.0) |
| Who died | 4 | (6.6) | 0 | (0.0) |
| Discontinued due to a vaccine-related AE | 1 | (1.6) | 1 | (5.3) |
N = Number of subjects randomized and vaccinated in the vaccination group
n = Number of subjects in each category
Determine by the investigator to be possibly, probably, or definitely related to the vaccine The same subject may appear in different categories, but counted only once in each category
At baseline, the VZV-specific gpELISA GMT was 205 (90% CI: 158, 267) and the IFN-γ ELISPOT GMC was 11 (90% CI: 7, 18). Both measures increased Postdose 4: gpELISA GMT was 262 (90% CI: 204, 336); IFN-γ ELISPOT GMC was 24 (90% CI: 14, 41). The primary hypothesis was met, as Postdose 4 immune responses were significantly higher than baseline for both gpELISA (GMFR=1.3 [90% CI: 1.1, 1.5], p=0.003) and IFN-γ ELISPOT (GMFR= 2.2 [90% CI: 1.4, 3.5], p=0.004).
Immunogenicity Analyses in ZVHT Recipients
| . | Postdose 1 . | Postdose 2 . | Postdose 3 . | Postdose 4 . |
|---|---|---|---|---|
| VZV gpELISA (n=59) | ||||
| GMT (90% CI) | 287 (219, 376) | 244 (187, 319) | 259 (202, 333) | 262 (204, 336) |
| GMFR (90% CI) | 1.4 (1.2, 1.6) | 1.2 (1.0, 1.5) | 1.3 (1.1, 1.5) | 1.3 (1.1, 1.5) |
| VZV IFN-γ ELISPOT (n=60) | ||||
| GMC (90% CI) | 20 (12, 32) | 18 (10, 31) | 24 (14, 40) | 24 (14, 41) |
| GMFR (90% CI) | 1.8 (1.2, 2.7) | 1.7 (1.1, 2.5) | 2.2 (1.5, 3.3) | 2.2 (1.4, 3.5) |
| . | Postdose 1 . | Postdose 2 . | Postdose 3 . | Postdose 4 . |
|---|---|---|---|---|
| VZV gpELISA (n=59) | ||||
| GMT (90% CI) | 287 (219, 376) | 244 (187, 319) | 259 (202, 333) | 262 (204, 336) |
| GMFR (90% CI) | 1.4 (1.2, 1.6) | 1.2 (1.0, 1.5) | 1.3 (1.1, 1.5) | 1.3 (1.1, 1.5) |
| VZV IFN-γ ELISPOT (n=60) | ||||
| GMC (90% CI) | 20 (12, 32) | 18 (10, 31) | 24 (14, 40) | 24 (14, 41) |
| GMFR (90% CI) | 1.8 (1.2, 2.7) | 1.7 (1.1, 2.5) | 2.2 (1.5, 3.3) | 2.2 (1.4, 3.5) |
GMT=geometric mean titer
GMC=geometric mean count
GMFR=geometric mean fold rise from Day 1 (baseline)
In the HM population, ZVHT had an acceptable safety profile and elicited statistically significant VZV-specific antibody and functional T-cell responses at 28 days Postdose 4.
Camacho:Merck: Research Funding. Off Label Use: This clinical research study examined the safety and immunogenicity of a heat-treated version of the licensed live-attenuated zoster vaccine (Zostavax) assessed in adults with hematologic malignancy. Betts:Merck: Research Funding. Wertheim:Merck: Research Funding. Zhao:Merck: Employment. Fernsler:Merck: Employment. Manoff:Merck: Employment. Annunziato:Merck: Employment.
Author notes
Asterisk with author names denotes non-ASH members.
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