V160 / Merck (MSD) - LARVOL DELTA

V160 2-Dose and 3-Dose Regimens in Healthy Cytomegalovirus (CMV) Seronegative Females (V160-002) (clinicaltrials.gov) - P2 | N=2200 | Completed | Sponsor: Merck Sharp & Dohme LLC | Phase classification: P2b ➔ P2

Phase classification • Cytomegalovirus Infection • Infectious Disease

Safety, efficacy, and immunogenicity of a replication-defective human cytomegalovirus vaccine, V160, in cytomegalovirus-seronegative women: a double-blind, randomised, placebo-controlled, phase 2b trial. (PubMed, Lancet Infect Dis) - P2b | "V160 was generally well tolerated and immunogenic; however, three doses of the vaccine did not reduce the incidence of primary CMV infection in CMV-seronegative women compared with placebo. This study provides insights into the design of future CMV vaccine efficacy trials, particularly for the identification of CMV infection using molecular assays."

Journal • P2b data • CNS Disorders • Cytomegalovirus Infection • Developmental Disorders • Fatigue • Infectious Disease • Pain • Psychiatry

Vaccination with a replication-defective cytomegalovirus vaccine elicits a glycoprotein B-specific monoclonal antibody repertoire distinct from natural infection. (PubMed, NPJ Vaccines) - "Few gB-specific neutralizing antibodies were isolated from V160 vaccinees and fewer antibodies had identifiable gB antigenic domain specificity compared to that of naturally-infected individuals. We also show that glycosylation of gB residue N73 may shield binding of gB-specific antibodies."

Journal • Cytomegalovirus Infection • Infectious Disease • Transplantation

Optimizing age specific strategies of vaccination for prevention of cytomegalovirus infection in the US using agent-based simulation. (PubMed, Epidemics) - "This study highlights the important need for a pediatric vaccination program in mitigating CMV in the United States. Our model is poised to investigate further location-based vaccine effectiveness questions in future planning of both clinical trials as well as eventual program implementation."

Journal • Cytomegalovirus Infection • Infectious Disease • Pediatrics

Safety, Tolerability, and Immunogenicity of V160, a Conditionally Replication-Defective Cytomegalovirus Vaccine, in Healthy Japanese Men in a Randomized, Controlled Phase 1 Study. (PubMed, Antibodies (Basel)) - P1 | "V160 was well tolerated, and no vaccine viral DNA shedding was observed. In conclusion, the immunogenicity and safety profile of V160 in Japanese participants was consistent with other populations."

Journal • P1 data • Cytomegalovirus Infection • Infectious Disease

Investigation into the use of gamma irradiated Cytodex-1 microcarriers to produce a human cytomegalovirus (HCMV) vaccine candidate in epithelial cells. (PubMed, J Biotechnol) - "Thorough aseptic rinsing of gamma irradiated Cytodex-1 prior to use can mitigate this impact and enable comparable process performance to heat-sterilized Cytodex-1. Though not fully a "ready-to-use" product for the HCMV V160 production process, utilization of Cytodex-1 microcarriers was possible without requiring heat sterilization, suggesting a potential path forward for large scale production of V160."

Journal • Cytomegalovirus Infection • Infectious Disease

Micro-flow imaging and flow virometry as preferred methods to monitor particulate matter for a human cytomegalovirus vaccine candidate. (PubMed, Biophys J) - No abstract available

Journal • Cytomegalovirus Infection

Enhancing the performance of the sterile filtration of vaccines: Proper selection of a prefilter and the role of hydrophobic interactions (ACS-Sp 2022) - "Although the sterile filtration of recombinant protein products is relatively straightforward, live attenuated viral (LAV) vaccines with large particle size (100 – 400 nm), such as the cytomegalovirus vaccine, pose significant challenges during sterile filtration with low yields and capacities...Particle yield for the model nanoparticle suspension was also increased by minimizing hydrophobic interactions by adding surfactants like Triton-X 100. This work provides important insights into the factors controlling sterile filtration of large particle vaccines as well as a framework for enhancing the yield and capacity of commercially available sterile filters."

Cytomegalovirus Infection

Novel adjuvants enhance immune responses elicited by a replication-defective human cytomegalovirus vaccine in nonhuman primates. (PubMed, Vaccine) - "In contrast, Advax did not activate any known inflammatory pathways and did not significantly impact gene expression pattern until day 7 post administration, suggesting a unique, non-inflammatory mechanism. These data warrant further exploration of Advax and LNP as adjuvants in clinical trials for vaccines desiring to elicit both humoral and T cell responses."

Clinical • IO biomarker • Journal • Cytomegalovirus Infection • Infectious Disease • CD4 • CD8

Cholesterol binds in a reversed orientation to TCRβ-TM in which its OH group is localized to the center of the lipid bilayer. (PubMed, J Mol Biol) - "An aromatic interaction with Y158 and hydrophobic interactions with V160 and L161 stabilize this reverse orientation. CS binds to the same site, explaining how it competes with cholesterol. Site-directed mutagenesis of the CARC-like motif disrupted the cholesterol/CS binding to TCRβ-TM, validating the NMR and MD results."

Journal • TCRB

[VIRTUAL] Double-Blind, Randomized, Placebo-Controlled Phase 2b Multicenter Trial of V160, a Replication-Defective Human Cytomegalovirus (CMV) Vaccine (IDWeek 2021) - "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."

Clinical • P2b data • Cytomegalovirus Infection • Infectious Disease • PCR

Safety, Tolerability, and Efficacy of the Human Cytomegalovirus Vaccine (V160) in Healthy Women 16 to 35 Years of Age (V160-002) (clinicaltrials.gov) - P2b; N=2200; Completed; Sponsor: Merck Sharp & Dohme Corp.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Cytomegalovirus Infection • Infectious Disease • PCR

Characterization of gH/gL/pUL128-131 pentameric complex, gH/gL/gO trimeric complex, gB and gM/gN glycoproteins in a human cytomegalovirus using automated capillary western blots. (PubMed, Vaccine) - "In our company ongoing Phase II clinical trial of whole-live virus HCMV vaccine (V160), the pentameric gH complex has been restored on the surface of live attenuated AD169 virus strain...This method is suitable for analyzing target proteins in multiple sample types including supernatants from infected cell culture, purification intermediates, concentration bulk, and the final vaccine product. In addition, the capillary western blot-based technology identified a previously unknown biochemical profile present in some HCMV viruses: triplet gH peaks of viral surface proteins in non-reducing environment, which could potentially present a new strategy for specificity and identity testing."

Journal • Cytomegalovirus Infection • Transplantation

A conditionally replication-defective cytomegalovirus vaccine elicits potent and diverse functional monoclonal antibodies in a phase I clinical trial. (PubMed, NPJ Vaccines) - P1 | "Sequence analysis indicated that V160 induced a class of gHgL antibodies expressing the HV1-18/KV1-5 germline genes in multiple subjects. This study provides valuable insights into primary targets for anti-HCMV antibodies induced by V160 vaccination."

Clinical • Journal • P1 data • Cytomegalovirus Infection • Infectious Disease

Safety, Tolerability, and Efficacy of the Human Cytomegalovirus Vaccine (V160) in Healthy Women 16 to 35 Years of Age (V160-002) (clinicaltrials.gov) - P2b; N=2200; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Trial primary completion date: May 2021 ➔ Oct 2020

Clinical • Trial primary completion date • Cytomegalovirus Infection • Infectious Disease • PCR

Saturation mutagenesis to improve the degradation of azo dyes by versatile peroxidase and application in form of VP-coated yeast cell walls. (PubMed, Enzyme Microb Technol) - "We used saturation mutagenesis to alter two amino acids in the catalytic tryptophan environment of VP (V160 and A260)...To allow multiple cycles of dye degradation, we immobilized VP on the surface of yeast cells and used washed cell wall fragments after lysis. VP embedded in the cell wall retained ∼70 % of its initial activity after 10 cycles of dye degradation each lasting 12 h, making this platform ideal for the bioremediation of environments contaminated with azo dyes."

Journal

Functional Evaluation and Genetic Evolution of Human T-cell Responses after Vaccination with a Conditionally Replication-Defective Cytomegalovirus Vaccine. (PubMed, J Infect Dis) - "V160 induced a genetically diverse and polyfunctional T-cell response and the data support further clinical development of V160 for prevention of CMV infection and congenital transmission."

IO Biomarker • Journal • Cytomegalovirus Infection • CD8

DNA methylation editing by CRISPR-guided excision of 5-methylcytosine. (PubMed, J Mol Biol) - "We also found that reactivation induced by dCas9-ROS1, as well as that achieved by two different CRISPR-based chromatin effectors (dCas9-VP160 and dCas9-p300), generally decreases with methylation density. Our results suggest that plant 5-meC DNA glycosylases are a valuable addition to the CRISPR-based toolbox for epigenetic editing."

Journal

A Replication Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection. (PubMed, J Virol) - "The vaccine, named V160, has been shown to be safe and immunogenic in HCMV-seronegative human subjects, eliciting both humoral and cellular immune responses (S...Importantly, vaccination can induce long lived memory B-cells at frequencies comparable to those seen in HCMV-seropositive subjects. We conclude that this vaccine is a promising candidate that warrants further clinical evaluation for prevention of congenital HCMV."

Journal • Cytomegalovirus Infection

Phase 1 Clinical Trial of a Conditionally Replication-Defective Human Cytomegalovirus (CMV) Vaccine in CMV-Seronegative Subjects. (PubMed, J Infect Dis) - P1; "V160 displayed an acceptable safety profile. Levels of neutralizing antibodies and T-cell responses in CMV-seronegative subjects were within ranges observed following natural CMV infection."

Clinical • Journal • P1 data

Role of atrial arrhythmia and ventricular response in atrial fibrillation induced atrial remodeling. (PubMed, Cardiovasc Res) - "The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodeling and novel considerations for ventricular rate-control."

Journal

Safety and Immunogenicity of the Human Cytomegalovirus (CMV) Vaccine (V160) in Healthy Japanese Men (V160-003) (clinicaltrials.gov) - P1; N=18; Completed; Sponsor: Merck Sharp & Dohme Corp.; Active, not recruiting ➔ Completed

Clinical • Trial completion

Mouse medulloblastoma driven by CRISPR activation of cellular Myc. (PubMed, Sci Rep) - "Three combined sgRNAs linked to dCas9-VP160 induced cellular Myc expression and large cell anaplastic MBs (CRISPR-Myc tumors) which recapitulated the molecular characteristics of mouse and human G3 MBs. The BET inhibitor JQ1 suppressed MYC expression in a human G3 MB cell line (HD-MB03) and CRISPR-Myc, but not in Retro-Myc MBs. This G3 MB mouse model in which Myc expression is regulated by its own promoter will facilitate pre-clinical studies with drugs that regulate Myc transcription."

Journal • Preclinical

Safety, Tolerability, and Efficacy of the Human Cytomegalovirus Vaccine (V160) in Healthy Women 16 to 35 Years of Age (V160-002) (clinicaltrials.gov) - P2b; N=2100; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Targeted Transgene Activation in the Brain Tissue by Systemic Delivery of Engineered AAV1 Expressing CRISPRa. (PubMed, Mol Ther Nucleic Acids) - "...To enable AAV packaging, we constructed minimal CRISPRa and CRISPRi transgenes by fusing catalytically inactive Staphylococcus aureus Cas9 (dSaCas9) to the transcriptional activator (VP64 and VP160) and repressor (KRAB and SID4X) domains along with truncated regulatory elements...Importantly, a single-dose intravenous administration of AAV1-PHP.B expressing CRISPRa was shown to achieve targeted transgene activation in the mouse brain. This proof-of-concept study will contribute to the development of a non-invasive, specific and potent AAV-CRISPR system for correcting transcriptional misregulation in broad brain areas and multiple neuroanatomical structures."

Journal