Safety and Immunogenicity Of Inactivated Varicella-Zoster Virus Vaccine In Adults With Hematologic Malignancies Receiving Treatment With Anti-CD20 Monoclonal Antibodies
Authors: McNeil Shelly , Betts Robert , Lawrence Steven , Velardi Andrea , Kimby Eva , Pagnoni Marco , Stek Jon , Zhao Yanli , Chan Ivan , Lee Ingi , Parrino Janie 
Published: October 2019

Abstract

Background
Herpes zoster (HZ) incidence is higher in patients with hematologic malignancies (HM) (25-100 cases/1000 person-years) than in the general population (3-5 cases/1000 person-years). This immunocompromised population can experience significant morbidity and occasional mortality from complications associated with reactivation of the varicella-zoster virus (VZV). In general, there is limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies, used in treatment of HM patients, on vaccine-related cell-mediated immune response. Due to the potential negative impact of anti-CD20 monoclonal antibodies on vaccine immunogenicity and efficacy, HM patients receiving anti-CD20 monoclonal antibodies have been excluded from prior inactivated VZV vaccine (inactivated-ZV) studies. This study evaluated the safety and immunogenicity of inactivated-ZV in HM patients receiving anti-CD20 monoclonal antibody therapy.

Methods
This was an open label, single arm, multicenter Phase I study of a 4-dose inactivated-ZV regimen (∼30 days between each dose) in patients ≥18 years old with HM receiving anti-CD20 monoclonal antibodies either as a single agent or in a combination chemotherapy regimen and not likely to undergo HCT (n=80). Blood samples were collected at baseline prior to dose 1 and 28 days postdose 4 to measure VZV-specific T-cell responses using interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that inactivated-ZV would elicit significant VZV-specific immune responses at ∼28 days postdose 4, with the statistical criterion being that the lower bound of the two-sided 90% confidence interval (CI) on the geometric fold rise (GMFR) be >1.0. All vaccinated patients were evaluated for adverse events (AE), including VZV-like rashes, through 28 days postdose 4.

Results
The 4-dose inactivated-ZV regimen elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28 days postdose 4 in the per-protocol population (GMFR = 4.34 [90% CI: 3.01, 6.24], p-value <0.001). As the lower bound of the 2-sided 90% CI for GMFR was >1.0, the pre-specified primary immunogenicity success criterion was met.
Overall, 85% (68/80) of patients reported ≥1 AEs, 44% (35/80) reported ≥1 injection-site AEs, and 74% (59/80) reported ≥1 systemic AEs. The most common injection-site AEs were pain (32%), erythema (31%), and swelling (26%). The most common systemic AEs were pyrexia (25%) and diarrhea (14%). Twelve patients (15%) experienced serious AEs, including one event determined by the investigator to be vaccine-related (convulsion: day 8 postdose 1). One patient experienced a fatal serious AE (Richter’s transformation to Hodgkin’s disease; day 34 postdose 1) assessed as not vaccine-related by the investigator. In general, the frequencies of AEs did not increase with subsequent doses of vaccine. No inactivated-ZV recipient had a rash that was PCR positive for VZV vaccine strain.

Conclusions
In adults with HM receiving anti-CD20 monoclonal antibodies, inactivated-ZV was well tolerated and elicited statistically significant VZV-specific T-cell responses ∼28 days postdose 4.

Disclosures:
McNeil: Merck: investigator Other, Research Funding. Betts:Merck: investigator Other, Research Funding. Lawrence:Merck: investigator Other, Research Funding. Velardi:Merck: investigator Other, Research Funding. Kimby:Merck: investigator Other, Research Funding. Pagnoni:Merck: Employment, Equity Ownership. Stek:Merck: Employment, Equity Ownership. Zhao:Merck: Employment, Equity Ownership. Chan:Merck: Employment, Equity Ownership. Lee:Merck: Employment, Equity Ownership. Parrino:Merck: Employment, Equity Ownership.