Clinical Development of a Cytomegalovirus DNA Vaccine: From Product Concept to Pivotal Phase 3 Trial

Smith, Larry; Wloch, Mary K.; Chaplin, Jennifer A.; Gerber, Michele; Rolland, Alain

doi:10.3390/vaccines1040398

Cited by 34 publications

(24 citation statements)

References 41 publications

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“…The vaccine is a formulation of two plasmids expressing gB and pp65 that are delivered in nanoparticles comprised of a nonionic triblock poloxamer, CRL1005, and a cationic surfactant, benzalkonium chloride. Preclinical development and animal testing of this vaccine has been reviewed elsewhere [68]. A phase I clinical trial evaluating the safety of ASP0113 found no serious adverse events in the 22 HCMV seropositive and 22 seronegative individuals immunized [69].…”

Section: Hcmv Vaccine Technologiesmentioning

confidence: 99%

Cytomegalovirus Vaccines: Current Status and Future Prospects

Anderholm

Bierle

Schleiss

2016

Drugs

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Congenital human cytomegalovirus (HCMV) infection can result in in severe and permanent neurological injury in newborns, and vaccine development is accordingly a major public health priority. HCMV can also cause disease in solid organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients, and a vaccine would be valuable in prevention of viremia and end-organ disease in these populations. Currently there is no licensed HCMV vaccine, but progress toward this goal has been made in recent clinical trials. A recombinant HCMV glycoprotein B (gB) vaccine has been shown to have some efficacy in prevention of infection in young women and adolescents, and provided benefit to HCMV-seronegative SOT recipients. Similarly, DNA vaccines based on gB and the immunodominant T-cell target, pp65 (ppUL83), have been shown to reduce viremia in HSCT patients. This review provides an overview of HCMV vaccine candidates in various stages of development, as well as an update on the current status of ongoing clinical trials. Protective correlates of vaccine-induced immunity may be different for pregnant woman and transplant patients. As more knowledge emerges about correlates of protection, the ultimate licensure of HCMV vaccines may reflect the uniqueness of the target populations being immunized.

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Section: Hcmv Vaccine Technologiesmentioning

confidence: 99%

Cytomegalovirus Vaccines: Current Status and Future Prospects

Anderholm

Bierle

Schleiss

2016

Drugs

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“…14 The safety and immunogenicity of ASP0113 has been demonstrated in healthy CMV-seronegative and CMV-seropositive adults in a phase 1 study, 15 and its efficacy and safety has been investigated in a randomized, double-blind, placebo-controlled, phase 2 study for the treatment of CMV in allogeneic HCT recipients. 2 ASP0113 is a bivalent DNA vaccine containing the plasmids VCL-6365 and VCL-6368 (1:1 mass ratio) that encode glycoprotein B (gB) and phosphoprotein 65 (pp65), formulated with poloxamer CRL1005 and benzalkonium.…”

Section: Introductionmentioning

confidence: 99%

“…2 ASP0113 is a bivalent DNA vaccine containing the plasmids VCL-6365 and VCL-6368 (1:1 mass ratio) that encode glycoprotein B (gB) and phosphoprotein 65 (pp65), formulated with poloxamer CRL1005 and benzalkonium. 14 The safety and immunogenicity of ASP0113 has been demonstrated in healthy CMV-seronegative and CMV-seropositive adults in a phase 1 study, 15 and its efficacy and safety has been investigated in a randomized, double-blind, placebo-controlled, phase 2 study for the treatment of CMV in allogeneic HCT recipients. 2 In this aforementioned study, there were no statistically significant differences in the primary endpoint (rate of initiation of CMV-specific AVTs) between transplant recipients treated with 5 doses of ASP0113 (5 mg) and those receiving placebo.…”

Section: Introductionmentioning

confidence: 99%

A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor

Vincenti

Budde

Merville

et al. 2018

American Journal of Transplantation

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Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA-based vaccine for the prevention of CMV-related mortality and end-organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double-blind, placebo-controlled study in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Transplant recipients were randomized (1:1) to receive 5 doses of ASP0113 (5 mg; n = 75) or placebo (n = 74) on Days 30/60/90/120/180 posttransplant, and they received prophylactic valganciclovir/ganciclovir 10-100 days posttransplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after the first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43-1.47; P = .307). There were similar numbers of transplant recipients with treatment-emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV-seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. ClinicalTrials.gov registration number: NCT01974206.

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“…This study warranted further investigation into CMV vaccines against gB 16 . In transplant recipients, plasmid DNA vaccines offer a number of benefits over other vaccine approaches: (1) improved safety profile compared to live attenuated viruses that may replicate to undesirable levels in immunocompromised patients; (2) no establishment of latency from viral reactivation leading to possible disease complications; (3) potential for inducing a T‐cell response critical for controlling CMV replication, unlike protein‐/peptide‐based vaccines; and (4) lack of susceptibility to neutralizing antivector immune responses generated from viral vector‐based vaccines, which would preclude repetitive injections 17 …”

mentioning

confidence: 99%

“…Immune responses to CMV include nonneutralizing antibodies to envelope gB and T‐cell responses to tegument phosphoprotein 65 (pp65) 18,19 . CMV vaccine research has focused on these antigens, but no vaccine has been licensed to date 17 . ASP0113 is a first‐in‐class, DNA‐based vaccine designed for the prevention of all‐cause mortality and CMV end‐organ disease in CMV‐seropositive allogeneic HCT recipients.…”

mentioning

confidence: 99%

Pharmacokinetics and Immunogenicity of ASP0113 in CMV‐Seronegative Dialysis Patients and CMV‐Seronegative and ‐Seropositive Healthy Subjects

Bonate

Sant

Cho

et al. 2020

Clinical Pharm in Drug Dev

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Cytomegalovirus (CMV) infection causes significant morbidity and mortality in immunocompromised transplant patients. ASP0113, a first-in-class DNA vaccine containing plasmids encoding CMV phosphoprotein 65 and glycoprotein B (gB), was evaluated in a phase 1b, subject-blinded study in CMV-seropositive (n = 13) and CMV-seronegative (n = 12) healthy and CMV-seronegative dialysis subjects (n = 12) randomized to ASP0113 or placebo. End points included pharmacokinetics, anti-gB antibody levels, phosphoprotein 65-specific T-cell responses measured by ex vivo enzyme-linked immune absorbent spot (ELISpot) assay and 10-day cultured ELISpot and Stat T-cell activation assays, and safety. ASP0113 concentrations peaked at 2-10 and 24-48 hours; the pharmacokinetics were similar across groups. No group demonstrated significant anti-gB antibody responses. T-cell responder rates in the cultured ELISpot assay were 8/12 (66.7%, 95%CI 35% to 90%) and 4/12 (33.3%, 95%CI 10% to 65%) in CMV-seronegative healthy subjects and dialysis patients, respectively, whereas ex vivo ELISpot assay response rates were 4/11 (36.4%, 95%CI 11% to 69%) and 0/12, respectively. Responses peaked at week 27, with lower magnitude observed in CMV-seronegative dialysis patients versus CMV-seronegative healthy subjects. No serious adverse events occurred; the most common adverse event in ASP0113-vaccinated patients was injection-site pain (64.9%). Some CMV-seronegative healthy subjects and dialysis patients had T-cell responses; no humoral responses were detected.

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Clinical Development of a Cytomegalovirus DNA Vaccine: From Product Concept to Pivotal Phase 3 Trial

Cited by 34 publications

References 41 publications

Cytomegalovirus Vaccines: Current Status and Future Prospects

Cytomegalovirus Vaccines: Current Status and Future Prospects

A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor

Pharmacokinetics and Immunogenicity of ASP0113 in CMV‐Seronegative Dialysis Patients and CMV‐Seronegative and ‐Seropositive Healthy Subjects

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