A Cytomegalovirus Vaccine for Transplantation: Are We Closer?

Go, Vera S; Pollard, Richard B.

doi:10.1086/588386

Cited by 6 publications

(3 citation statements)

References 25 publications

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“…New antiviral drugs [18], vaccines [19,20], and reconstitution of HCMV cellular immunity [21-23] should be considered when designing new models of HCMV disease prevention.…”

Section: Resultsmentioning

confidence: 99%

Differential outcome of neurological HCMV infection in two hematopoietic stem cell transplant recipients

et al. 2012

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BackgroundHuman cytomegalovirus (HCMV) infection of the central nervous system (CNS) is a rare but life threatening condition which may follow hematopoietic stem cell transplantation. Diagnosis, monitoring and treatment approaches rely on anecdotal reports.Case presentationsThe different outcomes of HCMV CNS disease in an adult and a pediatric T-cell depleted hematopoietic stem cell transplant (HSCT) recipient are reported. In the first case, HCMV encephalitis emerged in the context of simultaneous impairment of the T- and B-cell immunity. Antiviral treatment only reduced viral load in peripheral blood and the patient died. In the second case, an HCMV radiculopathy was observed and antiviral treatment was adjusted on the basis of intrathecal drug level. In addition, donor HCMV-specific cytotoxic T lymphocytes (CTLs) were infused. Viral load in the CNS decreased and the patient recovered from the acute event. In neither case were drug-resistant HCMV variants observed in blood or CNS samples.ConclusionsT-cell depleted HSCT appears a predisposing condition for CNS HCMV infection since never observed in other HSCT recipients at our center in the last 15 years. Intensive diagnostic approaches and timely aggressive combination treatments might improve clinical outcome in these patients.

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“…New antiviral drugs [18], vaccines [19,20], and reconstitution of HCMV cellular immunity [21-23] should be considered when designing new models of HCMV disease prevention.…”

Section: Resultsmentioning

confidence: 99%

Differential outcome of neurological HCMV infection in two hematopoietic stem cell transplant recipients

et al. 2012

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“…The timeline in Figure 1 integrates all of the key activities described above and illustrates both the typical and unanticipated factors that can impact product development timelines. A reasonably representative time frame ensued from product concept to completion of phase 1 testing and accordingly the indication of the favorable safety profile and demonstration of immunogenicity in humans [ 38 , 41 ], a vital first stage for a vaccine program. In contrast, the phase 2 trial in HCT recipients took an extended period of time to enroll, largely due to the novelty of the approach and the inherently-complex nature of conducting a vaccine trial in subjects with such underlying conditions and treatment-associated morbidity; furthermore, as described in Section 2.2 , the original premise was to vaccinate donors but due to the limited time donors were available prior to transplant, this proved impractical and this arm was discontinued while leaving the recipient-only arm open.…”

Section: Timeline Summary Of Asp0113 Development Historymentioning

confidence: 99%

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

et al. 2013

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2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV) DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB) and phosphoprotein 65 (pp65) formulated with a CRL1005 poloxamer and benzalkonium chloride (BAK) delivery system designed to enhance plasmid expression. The vaccine’s planned initial indication under investigation is for prevention of CMV reactivation in CMV-seropositive (CMV+) recipients of an allogeneic hematopoietic stem cell transplant (HCT). A randomized, double-blind placebo-controlled phase 2 proof-of-concept study provided initial evidence of the safety of this product in CMV+ HCT recipients who underwent immune ablation conditioning regimens. This study revealed a significant reduction in viral load endpoints and increased frequencies of pp65-specific interferon-γ-producing T cells in vaccine recipients compared to placebo recipients. The results of this endpoint-defining trial provided the basis for defining the primary and secondary endpoints of a global phase 3 trial in HCT recipients. A case study is presented here describing the development history of this vaccine from product concept to initiation of the phase 3 trial.

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“…An additional assay, the cultured IFN-γ ELISpot assay, was employed to evaluate whether the vaccine primed the memory T-cell response; this assay demonstrated a positive response to pp65 and/or gB in 68.2% (15 out of 22) of HCMV-seronegative subjects, including subjects who did not have detectable responses by ex vivo IFN-γ ELISpot assay or ELISA. These results suggest that the VCL-CB01 vaccine has the ability to prime antigen-specific T cells, with the capacity to proliferate and secrete IFN-γ on restimulation with antigen [43, 44], and that the cultured ELISpot assay appears to be more sensitive than the ex vivo ELISpot assay for the detection of vaccine-induced antigen-specific T-cell responses [42]. A limitation of the VCL-CB01 vaccine was the lack of gB antibody response in HCMV-seropositive subjects, although the vaccine boosted the existing pp65 T-cell response.…”

Section: What Has Gone Into People – An Update On the Status Of Recenmentioning

confidence: 99%

Update on the current status of cytomegalovirus vaccines

Sung

Schleiss

2010

Expert Review of Vaccines

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Human cytomegalovirus (HCMV) is ubiquitous in all populations, and is the most commonly recognized cause of congenital viral infection in developed countries. On the basis of the economic costs saved and the improvement in quality of life that could potentially be conferred by a successful vaccine for prevention of congenital HCMV infection, the Institute of Medicine has identified HCMV vaccine development as a major public health priority. An effective vaccine could potentially also be beneficial in preventing or ameliorating HCMV disease in immunocompromised individuals. Although there are no licensed HCMV vaccines currently available, enormous progress has been made in the last decade, as evidenced by the recently reported results of a Phase II trial of a glycoprotein B vaccine for the prevention of HCMV infection in seronegative women of childbearing age. HCMV vaccines currently in clinical trials include: glycoprotein B subunit vaccines; alphavirus replicon particle vaccines; DNA vaccines; and live-attenuated vaccines. A variety of vaccine strategies are also being examined in preclinical systems and animal models of infection. These include: recombinant vesicular stomatitis virus vaccines; recombinant modified vaccinia virus Ankara; replication-deficient adenovirus-vectored vaccines; and recombinant live-attenuated virus vaccines generated by mutagenesis of cloned rodent CMV genomes maintained as bacterial artificial chromosomes in Escherichia coli. In this article, we provide an overview of the current state of clinical trials and preclinical development of vaccines against HCMV, with an emphasis on studies that have been conducted in the past 5 years. We also summarize a number of recent advances in the study of the biology of HCMV, particularly with respect to epithelial and endothelial cell entry of the virus, which have implications for future vaccine design.

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A Cytomegalovirus Vaccine for Transplantation: Are We Closer?

Cited by 6 publications

References 25 publications

Differential outcome of neurological HCMV infection in two hematopoietic stem cell transplant recipients

Differential outcome of neurological HCMV infection in two hematopoietic stem cell transplant recipients

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

Update on the current status of cytomegalovirus vaccines

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