1048. Double-Blind, Randomized, Placebo-Controlled Phase 2b Multicenter Trial of V160, a Replication-Defective Human Cytomegalovirus (CMV) Vaccine

Abstract

Background Preventing congenital cytomegalovirus infection (CMVi) is an important unmet need. Natural maternal immunity to CMV acquired prior to pregnancy appears to reduce fetal transmission. In a Phase 1 trial, V160, a replication-defective CMV vaccine expressing the pentameric complex, induced humoral and cell-mediated immune (CMI) responses comparable to natural immunity. Methods Healthy, CMV-seronegative women aged 16–35 years were randomized 1:1:1 to receive double-blind V160 in a 3- or 2-dose regimen or placebo. Primary and secondary endpoints were efficacy in reducing the incidence of CMVi with 3-dose or 2-dose regimens of V160 vs placebo, respectively, using a fixed-event design. Monthly urine and saliva samples were collected to identify CMVi by polymerase chain reaction (PCR) with a single positive sample considered evidence of infection. Immunoglobulin G (IgG) binding to glycoprotein B (gB) and CMV-specific neutralizing antibody (NAb) were measured in all participants, and CMI responses were measured in a subset. Injection-site and systemic adverse events (AEs) were collected for 5 days and 14 days, respectively, after each vaccination and serious AEs were collected for the trial duration. Results 2200 women from 7 countries were enrolled (of 7458 screened). Over 80% of participants received all doses, and compliance with saliva and urine samples was > 95%. Vaccine efficacy (VE) of 42.4% (95% CI -13.5, 71.1%) was demonstrated in the 3-dose group vs placebo. In the 2-dose group, VE was -32.0% (95% CI -135.0, 25.0%). Both the quantity and duration of CMV shedding in urine and saliva among cases of CMVi decreased in the 3-dose, but not the 2-dose group vs placebo. Both V160 regimens elicited humoral and CMI responses detected by CMV-specific NAb, gB IgG, and ELISpot, which peaked at Month 7 and continued to be detectable at Month 24. Mild to moderate AEs were more frequently reported in V160 vs placebo recipients, but no vaccine-related serious AEs or deaths were reported. Conclusion V160 was well tolerated and immunogenic, but neither the 3-dose nor 2-dose regimen demonstrated significant efficacy against CMVi as defined in this trial. The quantity and duration of CMV shedding was reduced in the 3-dose group, suggesting V160 may improve immune control of viral replication after CMVi. Disclosures Rituparna Das, MD, Merck & Co, Inc. (Employee) Daniel Blazquez-Gamero, MD, MSD (Other Financial or Material Support, Fees for lectures in educational activities) Soren Gantt, MD, Altona Diagnostics (Research Grant or Support)Merck (Consultant, Grant/Research Support)Meridian Biosciences (Research Grant or Support)Moderna (Consultant, Research Grant or Support)VBI Vaccines Inc (Research Grant or Support) Oliver Bautista, PhD, Merck & Co, Inc. (Employee) Karen Beck, RN, BSN, Merck & Co, Inc. (Employee) Anthony Conlon, PhD, Merck & Co, Inc. (Employee) Daniel Rosenbloom, PhD, Merck & Co, Inc. (Employee) Dai Wang, PhD, Merck & Co, Inc. (Employee) Michael Ritter, BA, Merck & Co, Inc. (Employee) Beth Arnold, MS, Merck & Co, Inc. (Employee, Shareholder) Paula Annunziato, MD, Merck & Co, Inc. (Employee) Kevin Russell, MD, MTM&H, Merck & Co., Inc. (Employee, Shareholder)

Safety, Tolerability, and Immunogenicity of V160, a Conditionally Replication-Defective Cytomegalovirus Vaccine, in Healthy Japanese Men in a Randomized, Controlled Phase 1 Study

“…This is particularly important given the higher risk of congenital CMV in younger people in Japan and in the context of ethnic differences in the risk of congenital CMV infection being observed in the past [ 7 ]. The NAb titer achieved in CMV-seronegative participants using a V160 dose comprising 100 units and aluminum phosphate adjuvant was also consistent with previous observations [ 13 , 16 ]. However, the vaccine administered in this study was lyophilized, whereas the U.S. study used a frozen preparation, and the assay used to make the assessments in this study has key differences.…”

“…Post-vaccination NAb levels in seronegative participants in this study were consistent with baseline NAb levels among CMV-seropositive individuals in a previous study in the U.S., but were below mean baseline levels observed in CMV-seropositive participants [ 13 ]. However, the results in seronegative participants are consistent with observations in a similar population enrolled in a phase 2b study in the U.S. [ 16 ]. In the absence of an immunologic correlate of protection for the prevention of maternal–fetal CMV transmission, natural immunity offers a reasonable benchmark for evaluating the efficacy of V160 because immunity to CMV, and an early response to primary CMV infection, can protect against maternal–fetal CMV transmission [ 7 ].…”

Vaccination with a disabled infectious single cycle cytomegalovirus vaccine elicits a distinct glycoprotein B-specific monoclonal antibody repertoire compared to that of naturally-infected individuals

“…Addition of other glycoprotein complexes to the HCMV vaccine, such as the pentameric complex, while a promising approach, have not yet demonstrated increased vaccine efficacy 29 . The V160 DISC vaccine showed 42% reduction of infection in individuals vaccinated with 3 doses in a recent phase II trial 14 . Our study leveraged the opportunity to evaluate the monoclonal antibody repertoire elicited by vaccination with a replication defective vaccine virus against the main viral fusogen, gB, compared to that elicited by natural infection.…”

“…Human subjects and isolation of gB-specific monoclonal antibodies: The V160 vaccine is a disabled live attenuated virus based on the AD169 virus (gB 2 genotype) that contains a repaired pentameric complex, recently tested in a phase 2 study. 14 HCMV seronegative women were vaccinated with either a two or three dose regimen of the V160 vaccine. Six random individuals are included in this study (3 vaccinated intramuscular with 30 U V160 and 3 vaccinated intradermal with 30 U V160).…”

“…In follow up studies of the partially protective gB/MF59 vaccine clinical trial, we determined that IgG binding to cell-associated conformation of gB, but not the soluble gB antigen, was a correlate of protection against HCMV acquisition in gB/MF59 vaccinees 5 , indicating the importance of antibody binding to the native-like gB conformation in their ability to mediate protection and the need to further define antibodies that recognize this conformation of gB to aid in immunogen design. Interestingly, the disabled infectious single cycle (DISC) V160 vaccine also achieved partial efficacy against HCMV acquisition with a vaccine efficacy of 42% in a phase 2 trial 14 , indicating that this vaccine which displayed all HCMV glycoproteins in a single-round infection was similar to that of the gB immunogen alone. Studies of adding the PC to gB immunogens also did not achieve vaccine efficacy in nonhuman primate models 15 .…”