Phase 1 Clinical Trial of a Replication-Defective Human Cytomegalovirus (CMV) Vaccine

Abstract

BackgroundCongenital CMV remains an unmet medical need worldwide. Naturally acquired CMV immunity in women prior to pregnancy has been shown effective in reducing maternal-fetal transmission. V160 is engineered as a replication-defective CMV, and its replication in culture is controlled by a synthetic chemical. V160 can’t replicate in humans but it maintains all virological properties for presentation of viral antigens, including gH/gL/pUL128-131 pentameric complex, important for potent neutralizing antibodies (NABs).MethodsApproximately 190 CMV seronegative and seropositive adults at study entry received 3 doses of V160 or placebo administered via intramuscular (IM) or intradermal (ID) route on Day 1, Month 1, and Month 6. Four antigen levels (10, 30, 100, and 250 units per dose) formulated with or without aluminum phosphate adjuvant were evaluated. In each vaccination group, approximately 10 and 4 subjects received study vaccine and placebo, respectively. Injection site and systemic adverse events (AEs) were collected for 14 days after each vaccination. Serious AEs (SAEs) were assessed up to Month 18. Viral shedding (urine and saliva) were monitored up to Month 12. CMV-specific NABs and cell-mediated immune responses (CMI) were measured prior and 1 month after each vaccination, and at Months 12 and 18.ResultsDuring the study, no serious AEs were reported and only one CMV seropositive subject had non-vaccine type viral shedding. In both seronegative and seropositive cohorts, proportion of subjects who reported injection site AEs was higher in V160 recipients than placebo controls. Proportion of subjects who reported systemic AEs was comparable across V160 doses/formulations and placebo. In the CMV seronegative cohort, immune responses increased with incremental dosing. More importantly, recipients of V160 from several dose levels mounted NAB and CMI responses at 1 month post dose 3 (PD3) that were comparable to baseline levels measured in seropositive subjects.ConclusionV160 had acceptable safety profile across all dose levels and formulations studied; Vaccine was immunogenic and elicited NAB and CMI responses at 1 month PD3 that were comparable to natural CMV infection.Disclosures S. Adler, Merck: Investigator, Research grant. N. Lewis, Merck: Employee, Salary. A. Conlon, Merck: Employee, Salary. M. Christiansen, Merck: Investigator, Research grant. M. S. Al-Ibrahim, Merck: Investigator, Research grant R. Rupp, Merck: Investigator, Research grant. T. M. Fu, Merck: Employee, Salary. O. Bautista, Merck: Employee, Salary. H. Tang, Merck: Employee, Salary.T. Culp, Merck: Employee, Salary. R. Das, Merck: Employee, Salary. K. Beck, Merck: Employee, Salary. G. Tamms, Merck: Employee, Salary. L. Musey, Meck: Employee, Salary.

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

“…The vaccine and a placebo were compared in a low-, intermediate-, and high-dose comparison study, in both CMVseronegative and -seropositive individuals, with or without Merck aluminum phosphate adjuvant (MAPA). These data have not been published but were recently reported (107). V160 combined with MAPA adjuvant induced neutralizing antibodies after 3 doses at 0, 1, and 6 months.…”

A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection

“…This replication-defective modified AD169 strain, named V160, which contains a repaired UL131A gene locus, expresses all relevant HCMV antigens including the PC, whereby its conditional replication deficiency is based on the addition of a synthetic compound [100]. V160 was proven to be tolerable and immunogenic in healthy adults and conferred humoral and cell-mediated immune responses that were comparable to baseline levels measured in seropositive subjects [101]. Although the vaccine is advancing to a phase 2b clinical trial in healthy seronegative women with direct exposure to young children (NCT03486834), a major challenge in advancing V160 beyond phase II is the need to use human epithelial cells (EC) for its production [102,103].…”

Cytomegalovirus infection in liver-transplanted children

“…Virus-like particles consisting of a fusion product of extracellular domain glycoprotein B and vesicular stomatitis virus G-protein induced high titres of neutralizing antibodies[ 81 ]. Live-attenuated vaccine has shown a good safety profile, inducing both humoural and cell-mediated immunity, and reducing the incidence of severe infection[ 82 , 83 ]. However, vaccines still fail to prevent infection in seronegative solid organ transplant recipients.…”

“…However, vaccines still fail to prevent infection in seronegative solid organ transplant recipients. A disabled infectious single cycle vaccine induced neutralizing antibodies and cell-mediated immunity against CMV infection in non-human primates and had an acceptable safety profile[ 83 ]. Peptide-based, DNA-based, and vector vaccines are currently under investigation in phase I clinical trials[ 84 , 85 ].…”