A plasmid dna vaccine against cytomegalovirus cmv is in a. Cytomegalovirus cmv is a ubiquitous dna herpesvirus. This study will evaluate the safety, tolerability, and efficacy of human cytomegalovirus cmv vaccine v160 administered in a 2dose or 3dose regimen in. March 18, 2009 an experimental vaccine may curb cytomegalovirus in women, which might reduce cmvrelated birth defects in their children thats according to a. Cytomegalovirus infection emerging treatments bmj best. May 05, 2018 cytomegalovirus cmv is a doublestranded dna virus and is a member of the herpesviridae family. Between june 20 and february 2014, astellas conducted a phase 2, openlabel. A novel therapeutic cytomegalovirus dna vaccine in. The vrppp65 vaccine has entered phase 1 trials in humans, administered in a trivalent formulation with gb and ie1 ul123 vrps. In the absence of an adequate hostderived immune response, this fine balance of permitting viral reactivation without causing pathogenesis is disrupted, and hcmv can subsequently cause invasive disease and an array of. The vaccine contains plasmids encoding cytomegalovirus glycoprotein b and phosphoprotein 65 formulated with poloxamer crl1005 and. Vclcb01, a candidate cmv dna vaccine containing plasmids encoding cmv.
Dna vaccine, human cytomegalovirus, phos phoprotein 65 pp65. Cytomegalovirus cmv infectionreactivation is a serious complication after hematopoietic cell transplantation hct. Asp01 previously known as vclcb01 and transvax is a dna vaccine against cmv that was developed by vical corporation and. A dnabased vaccine for the prevention of human cytomegalovirus. The eight species in this genus include the type species, human betaherpesvirus 5 hcmv, human cytomegalovirus, hhv5, which is the species that infects humans. Cytomegalovirus cmv from the greek cyto, cell, and megalo, large is a genus of viruses in the order herpesvirales, in the family herpesviridae, in the subfamily betaherpesvirinae. Jan 11, 2018 cytomegalovirus cmv is a common herpes virus that lies dormant in the body and spreads through bodily fluids. Dna vaccine as a candidate for immunization against congenital cmv. Current status and future prospects, abstract congenital human cytomegalovirus hcmv infection can result in severe and permanent neurological injury in newborns, and vaccine development is accordingly a major public health priority.
Progress toward development of a vaccine against congenital. T1 update on the current status of cytomegalovirus vaccines. A dnabased vaccine for the prevention of human cytomegalovirusassociated diseases. As noted above, pp65 has also been expressed in a dna vaccine, and is currently being evaluated in a phase ii study in bmt recipients, coadministered in a bivalent formulation with gb dna vaccine. N2 human cytomegalovirus hcmv is ubiquitous in all populations, and is the most commonly recognized cause of congenital viral infection in developed countries. 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. The first strains of virus were isolated independently in the mid 1950s by smith, 1 rowe et al, 2 and weller et al. Congenital cytomegalovirus disease is an unsolved public health problem, unlikely to be solved by means other than immune prophylaxis.
Letermovir aic246 letermovir, an oral anticmv compound that targets the viral terminase complex, significantly decreased cmvdna copy number from baseline in a small, openlabel, proof of concept study. The 235kb genome encodes at least 165 proteins, but cmv vaccine research has focused on a limited number of viral proteins that dominate cellular or humoral immune responses during natural infection. Vbi is developing a prophylactic vaccine to prevent cytomegalovirus cmv infection. Vbi recently completed a phase i trial that evaluated safety, tolerability, and also immunological proof of concept in humans by measuring cmv neutralizing antibodies in fibroblasts and epithelial. It can cause blindness and other serious problems if youre hivpositive.
Cytomegalovirus cmv infection symptoms and causes mayo. Vical, san diego, ca, usa or placebo before conditioning and at 1, 3, and 6 months after transplantation. A dna based vaccine for the prevention of human cytomegalovirus associated diseases. Sera from 168 anticmv iggpositive and 100 seronegative subjects were used to evaluate. Poxvirus vectored cytomegalovirus vaccine to prevent cytomegalovirus viremia in transplant recipients. We show proof of concept for an immunotherapeutic cytomegalovirus vaccine. Cmv dna vaccine candidate utilizing the first two of these strategies. Human cytomegalovirus hcmv is the leading cause of congenital viral infection and mental retardation.
The optimal composition for a cmv vaccine remains to be defined but trials continue with the gb vaccine and others. Hence, careful diagnosis of primary infection is required in the pregnant woman based on the. A novel therapeutic cytomegalovirus dna vaccine in allogeneic haemopoietic stemcell transplantation. Vaccination against the human cytomegalovirus sciencedirect. The first strains of virus were isolated independently in the mid 1950s by smith,1 rowe et al,2 and weller et al. Cytomegalovirus cmv is among the largest and most complex of the known viruses that cause human disease. Cytomegalovirus antigen pp65 an overview sciencedirect. Cytomegalovirus cmv is a common herpes virus that lies dormant in the body and spreads through bodily fluids. Kharfandabaja ma, boeckh m, wilck mb, langston aa, chu ah, wloch mk. Pcrbased assays for the detection of cmv dna in saliva or urine from. The other family members include herpes simplex virus type 1 hsv1 or hhv1 and herpes simplex virus type 2 hsv2 or hhv2, varicella zoster virus vzv, human herpes virus hhv6, hhv7, and hhv8.
Candidate vaccines in clinical evaluation include live attenuated, protein subunit, dna, and viralvectored approaches. Cytomegalovirus was first observed by german pathologist hugo ribbert in 1881 when he noticed enlarged cells with enlarged nuclei present in the cells of an infant. Once infected, your body retains the virus for life. Jan 10, 2012 in the lancet infectious diseases, mohamed kharfandabaja and colleagues describe a phase 2, placebocontrolled trial1 of a therapeutic cytomegalovirus dna vaccine transvax. Safety of asp01, a cytomegalovirus dna vaccine, in. Clinical endpoint of congenital hcmv vaccination trials. A cytomegalovirus vaccine is a vaccine to prevent cytomegalovirus cmv infection or to prevent it reactivation in those who are already infected. Dna vaccines expressing the guinea pig cytomegalovirus gpcmv homologs of the glycoprotein b gb and. Occurrence and duration of episodes of cytomegalovirus viraemia were significantly reduced when cytomegalovirusseropositive. A dnabased vaccine for the prevention of human cytomegalovirusassociated diseases abstract multiple lines of evidence indicate that in the transplant population human cytomegalovirus hcmv infection and its associated diseases are controlled by humoral and cellular immune responses similar to those that arise in asymptomatic, healthy indi. Finally, the capacity of cmv to reinfect immune individuals has led several investigators to propose cmv as a vaccine vector for other agents. Women who develop an active cmv infection during pregnancy can pass the virus to their babies, who might then. This study will evaluate the safety, tolerability, and immunogenicity of various doses, formulations, and routes of administration of human cytomegalovirus hcmv vaccine v160 administered in a 3dose regimen in healthy adults.
Epidemiology agents are ubiquitous no seasonality us adult seroprevalence cmv 58. Sera from 168 anticmv iggpositive and 100 seronegative subjects were used to evaluate the antigb. Most people dont know they have cmv because it rarely causes problems in healthy people if youre pregnant or if your immune system is weakened, cmv is cause for concern. Between june 20 and february 2014, astellas conducted a phase 2, openlabel, uncontrolled, threecenter trial to. As with other herpesviruses, it becomes latent after a primary infection but can reactivate with renewed viral shedding. Diagnosis and management of human cytomegalovirus infection. In the lancet infectious diseases, mohamed kharfandabaja and colleagues describe a phase 2, placebocontrolled trial1 of a therapeutic cytomegalovirus dna vaccine transvax. A novel therapeutic cytomegalovirus dna vaccine in allogeneic. This article summarizes the status of the candidate vaccines. Antigen selection vical initiated development of a cmv dna vaccine for transplant recipients in 2002 by first. The replicon vaccine included gb and the t cell targets phosphoprotein pp65 and immediate early ie1 while the dna vaccine was given with a new adjuvant and included gb and pp65. Preemptive treatment of cytomegalovirus infection in kidney transplant recipients with letermovir. Cytomegalovirus vaccines under clinical development. Addressing this hypothesis, a phase iii trial assessing the efficacy of a bivalent cmv dna vaccine asp01, encoding both gb and pp65, to prevent mortality in seropositive transplant recipients is ongoing and, in phase ii studies, elicited robust, pp65specific.
Most people dont know they have cmv because it rarely causes problems in healthy people. Astellas and vical announce topline results for phase 3 trial of cytomegalovirus vaccine. Oct 28, 2016 cytomegalovirus cmv infectionreactivation is a serious complication after hematopoietic cell transplantation hct. Clinical development of a cytomegalovirus dna vaccine. Challenges in developing a vaccine include adeptness of cmv in evading the immune system and limited animal models. Health care professionals diagnose cmv infections by culturing the virus, detecting cmv dna from the infected individual, or detecting cmv antibodies. In those vaccines, immune responses primed with a dna vaccine encoding. Occurrence and duration of episodes of cytomegalovirus viraemia were significantly reduced when cytomegalovirus. Congenital cytomegalovirus cmv disease is the leading cause of permanent disability in neonates in the united states. Hence, careful diagnosis of primary infection is required in the pregnant woman. For this purpose, an enzymelinked immunosorbent assay elisa with a recombinant cmv gb molecule as the antigen was evaluated. An effective cytomegalovirus cmv vaccine could prevent the majority of birth defects caused by congenital cmv infections.
Safety, tolerability, and immunogenicity of the human. The dna vaccine asp01 contains two plasmids encoding cmv antigens glycoprotein b and tegument phosphoprotein 65 that stimulate humoral and cellular immunity. They find that in contrast to aged individuals where cmv infection decreased response to flu vaccine, cmv infection actually. Cytomegalovirus cmv is related to the herpes virus that gives you cold sores. I am a paid consultant to almost all of the cmv vaccine projects discussed here and thus have multiple conflicts. In the absence of an adequate hostderived immune response, this fine balance of permitting viral reactivation without causing pathogenesis is disrupted, and hcmv can subsequently cause invasive disease and. Addressing this hypothesis, a phase iii trial assessing the efficacy of a bivalent cmv dna vaccine asp01, encoding both gb and pp65, to prevent mortality in seropositive transplant recipients is ongoing and, in phase ii studies, elicited robust, pp65specific t cell responses and late, gbspecific b cell responses.
Cytomegalovirus infection enhances the immune response to. In preclinical studies of hcmv gb dna vaccines in mice, both the fulllength gb, as well as a truncated, secreted form expressing amino acids 1680 of a total of 906 gb residues, were evaluated. Dna plasmids vical, inovio selfreplicating rna glaxosmithkline peptides city of hope dense bodies vaccine project management germany viruslike particles variations bio, redbiotech soluble pentamers humabs 30 nonliving cmv vaccines in development. Apr 03, 2018 this study will evaluate the safety, tolerability, and efficacy of human cytomegalovirus cmv vaccine v160 administered in a 2dose or 3dose regimen in healthy seronegative women 16 to 35 years of age. Vical, san diego, ca, usa for patients undergoing haemopoietic stemcell transplantation.
Cytomegalovirus cmv is a doublestranded dna virus and is a member of the herpesviridae family. Scientific and regulatory considerations for efficacy. Measurement of antibody to cytomegalovirus cmv glycoprotein b gb is valuable in the assessment of the antibody response to infection and to gbcontaining vaccines. Each treatment arm of 10 participants will be accompanied by a placebo arm of 4 participants. Cytomegalovirus cmv is a dna herpesvirus that is common worldwide. Rhesus cytomegalovirus rhcmv infection of macaques exhibits strong similarities to human cmv hcmv persistence and pathogenesis. Scientific and regulatory considerations for efficacy studies. Neutralizing activity of saliva against cytomegalovirus. Development of a vaccine has been hampered by low awareness of the problem, which is caused by the often delayed detection of abnormalities after birth.
Enzymelinked immunosorbent assay for measurement of. Pdf a dnabased vaccine for the prevention of human. Dna vaccination is a technique for protecting against disease by injection with genetically engineered plasmid containing the dna sequence encoding the antigens against which an immune response is sought so cells directly produce an antibody, producing a protective immunological response. A final expression approach that has been applied to hcmv gb is dna vaccination. Dna vaccine protects against cytomegalovirus cmv oxford. Cytomegalovirus cmv has long been thought of as a sleeper agentpresent in a latent form in most people but dangerous when activated in immunosuppressed individuals. Cytomegalovirus cmv is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. Hcmv infection, while causing asymptomatic infections in most immunocompetent subjects, can be transmitted during pregnancy from the mother with primary and also recurrent infection to the fetus.
Proofofconcept testing of the vaccine in a phase 2 trial has been completed and the vaccine is expected to enter a pivotal phase 3 trial sponsored by astellas pharma, incorporated hereafter astellas. Mar 03, 2020 triplex vaccine was developed to enhance cytomegalovirus cmvspecific t cells and prevent cmv reactivation early after hematopoietic stem cell transplant hct. Cytomegalovirus vaccines clinical infectious diseases. Poxvirus vectored cytomegalovirus vaccine to prevent. A dna vaccine therefore offers the potential for tcell inducing qualities reminiscent of a live virus vaccine with the safety profile of a protein subunit vaccinean ideal vaccine profile for transplant recipients. Years later, between 1956 and 1957, thomas huckle weller together with smith and rowe independently isolated the virus, known thereafter as cytomegalovirus.
Update on the current status of cytomegalovirus vaccines. Its dna genome is approximately 230 kb in size, the largest among known human viruses, and consists of unique long ul and unique short us segments, each of which is flanked by inverted repeats rl and rs. A clinical trial using a bivalent dna vaccine dna encoding gb and pp65 induced antibodies and cellular immune responses in adult volunteers that included longterm tlymphocyte memory 625. Following primary infection, human cytomegalovirus hcmv establishes lifelong latency and periodically reactivates without causing symptoms in healthy individuals. Cmv is a leading cause of prenatal developmental delays. Shedding can occur from multiple sites and for prolonged periods of time. Our trial is the first proof of concept for a cytomegalovirus vaccine in a haemopoietic stemcell transplantation setting, the third to show proof of concept in any transplantation setting, and is the second plasmid dna vaccine to show proof of concept against an infectious disease pathogen. Virology double stranded dna viruses low mutation rate enveloped viruses labile in the environment 2. A phase ii study of a deoxyribonucleic acid dna vaccine expressing gb and structural protein pp65 suggested promise in renal transplant recipients, but a recent phase iii study of this vaccine in hsct transplant patients did not meet its endpoints of reducing overall mortality and cmv endorgan disease, or of time to cmv viremia or first use. Antiviral treatments may improve the prognosis in some patients with cytomegalovirus infections.
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