A plasmid dna vaccine against cytomegalovirus cmv is in a. 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. Vical, san diego, ca, usa for patients undergoing haemopoietic stemcell transplantation. Epidemiology agents are ubiquitous no seasonality us adult seroprevalence cmv 58. A dnabased vaccine for the prevention of human cytomegalovirus. I am a paid consultant to almost all of the cmv vaccine projects discussed here and thus have multiple conflicts. T1 update on the current status of cytomegalovirus vaccines. Cytomegalovirus infection emerging treatments bmj best. Asp01 previously known as vclcb01 and transvax is a dna vaccine against cmv that was developed by vical corporation and. 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. Once infected, your body retains the virus for life. For this purpose, an enzymelinked immunosorbent assay elisa with a recombinant cmv gb molecule as the antigen was evaluated. 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. 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.
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. Scientific and regulatory considerations for efficacy studies. Progress toward development of a vaccine against congenital. May 05, 2018 cytomegalovirus cmv is a doublestranded dna virus and is a member of the herpesviridae family.
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. Immunogenicity and protective efficacy of dna vaccines expressing. 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. 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. 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. Challenges in developing a vaccine include adeptness of cmv in evading the immune system and limited animal models. Cytomegalovirus cmv infectionreactivation is a serious complication after hematopoietic cell transplantation hct. 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. A dnabased vaccine for the prevention of human cytomegalovirusassociated diseases. Safety, tolerability, and immunogenicity of the human. Dna vaccine as a candidate for immunization against congenital cmv. 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.
Vical, san diego, ca, usa or placebo before conditioning and at 1, 3, and 6 months after transplantation. In those vaccines, immune responses primed with a dna vaccine encoding. Dna vaccine, human cytomegalovirus, phos phoprotein 65 pp65. A final expression approach that has been applied to hcmv gb is dna vaccination. This study will evaluate the safety, tolerability, and efficacy of human cytomegalovirus cmv vaccine v160 administered in a 2dose or 3dose regimen in. As with other herpesviruses, it becomes latent after a primary infection but can reactivate with renewed viral shedding. Shedding can occur from multiple sites and for prolonged periods of time. 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. Vbi is developing a prophylactic vaccine to prevent cytomegalovirus cmv infection. We show proof of concept for an immunotherapeutic cytomegalovirus vaccine. Congenital cytomegalovirus disease is an unsolved public health problem, unlikely to be solved by means other than immune prophylaxis. 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. Between june 20 and february 2014, astellas conducted a phase 2, openlabel, uncontrolled, threecenter trial to.
Hence, careful diagnosis of primary infection is required in the pregnant woman based on the. A cytomegalovirus vaccine is a vaccine to prevent cytomegalovirus cmv infection or to prevent it reactivation in those who are already infected. Congenital cytomegalovirus cmv disease is the leading cause of permanent disability in neonates in the united states. Cytomegalovirus vaccines under clinical development. Clinical development of a cytomegalovirus dna vaccine. Safety of asp01, a cytomegalovirus dna vaccine, in. Years later, between 1956 and 1957, thomas huckle weller together with smith and rowe independently isolated the virus, known thereafter as cytomegalovirus. Most people dont know they have cmv because it rarely causes problems in healthy people. A novel therapeutic cytomegalovirus dna vaccine in allogeneic haemopoietic stemcell transplantation. Cytomegalovirus cmv is among the largest and most complex of the known viruses that cause human disease. Women who develop an active cmv infection during pregnancy can pass the virus to their babies, who might then. Finally, the capacity of cmv to reinfect immune individuals has led several investigators to propose cmv as a vaccine vector for other agents. Cytomegalovirus cmv is related to the herpes virus that gives you cold sores.
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. Cytomegalovirus antigen pp65 an overview sciencedirect. Cytomegalovirus cmv is a ubiquitous dna herpesvirus. Candidate vaccines in clinical evaluation include live attenuated, protein subunit, dna, and viralvectored approaches. Each treatment arm of 10 participants will be accompanied by a placebo arm of 4 participants. The first strains of virus were isolated independently in the mid 1950s by smith,1 rowe et al,2 and weller et al. Neutralizing antibodies in saliva may protect against maternal cmv infection by blocking viral entry into oral epithelial cells, but the antibody response to cmv in the saliva following natural infection is not well characterized. Vclcb01, a candidate cmv dna vaccine containing plasmids encoding cmv. 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. Poxvirus vectored cytomegalovirus vaccine to prevent.
Sera from 168 anticmv iggpositive and 100 seronegative subjects were used to evaluate the antigb. The first strains of virus were isolated independently in the mid 1950s by smith, 1 rowe et al, 2 and weller et al. This article summarizes the status of the candidate vaccines. Dna vaccine protects against cytomegalovirus cmv oxford. Following primary infection, human cytomegalovirus hcmv establishes lifelong latency and periodically reactivates without causing symptoms in healthy individuals. Poxvirus vectored cytomegalovirus vaccine to prevent cytomegalovirus viremia in transplant recipients. 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. Cytomegalovirus infection enhances the immune response to. A dna based vaccine for the prevention of human cytomegalovirus associated diseases. Diagnosis and management of human cytomegalovirus infection. Human cytomegalovirus hcmv is the leading cause of congenital viral infection and mental retardation. The pp65 protein is a major target of the cytotoxic tcell response. 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.
Astellas and vical announce topline results for phase 3 trial of cytomegalovirus vaccine. Jan 11, 2018 cytomegalovirus cmv is a common herpes virus that lies dormant in the body and spreads through bodily fluids. Occurrence and duration of episodes of cytomegalovirus viraemia were significantly reduced when cytomegalovirusseropositive. The optimal composition for a cmv vaccine remains to be defined but trials continue with the gb vaccine and others. In some respects human cytomegalovirus research has moved as slowly as the cytopathic effect of the agent in tissue culture. It can cause blindness and other serious problems if youre hivpositive. 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. Clinical endpoint of congenital hcmv vaccination trials. Preemptive treatment of cytomegalovirus infection in kidney transplant recipients with letermovir. The vaccine contains plasmids encoding cytomegalovirus glycoprotein b and phosphoprotein 65 formulated with poloxamer crl1005 and. Between june 20 and february 2014, astellas conducted a phase 2, openlabel. Numerous phase 1 and phase 2 trials have been conducted with several cmv vaccine candidates but a. Virology double stranded dna viruses low mutation rate enveloped viruses labile in the environment 2. Cmv is a leading cause of prenatal developmental delays.
The dna vaccine asp01 contains two plasmids encoding cmv antigens glycoprotein b and tegument phosphoprotein 65 that stimulate humoral and cellular immunity. Cmv dna vaccine candidate utilizing the first two of these strategies. Kharfandabaja ma, boeckh m, wilck mb, langston aa, chu ah, wloch mk. Cytomegalovirus cmv is a dna herpesvirus that is common worldwide. 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. 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. Hence, careful diagnosis of primary infection is required in the pregnant woman. Cytomegalovirus cmv is a doublestranded dna virus and is a member of the herpesviridae family. Oct 28, 2016 cytomegalovirus cmv infectionreactivation is a serious complication after hematopoietic cell transplantation hct. Enzymelinked immunosorbent assay for measurement of.
Scientific and regulatory considerations for efficacy. 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. Vaccination against the human cytomegalovirus sciencedirect. Cytomegalovirus cmv infection symptoms and causes mayo. Neutralizing activity of saliva against cytomegalovirus. N2 human cytomegalovirus hcmv is ubiquitous in all populations, and is the most commonly recognized cause of congenital viral infection in developed countries.
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. Cytomegalovirus vaccines clinical infectious diseases. Occurrence and duration of episodes of cytomegalovirus viraemia were significantly reduced when cytomegalovirus. A novel therapeutic cytomegalovirus dna vaccine in.
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. Sera from 168 anticmv iggpositive and 100 seronegative subjects were used to evaluate. Measurement of antibody to cytomegalovirus cmv glycoprotein b gb is valuable in the assessment of the antibody response to infection and to gbcontaining vaccines. Cytomegalovirus cmv is a common herpes virus that lies dormant in the body and spreads through bodily fluids. 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. 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. Antigen selection vical initiated development of a cmv dna vaccine for transplant recipients in 2002 by first. Pcrbased assays for the detection of cmv dna in saliva or urine from. An effective cytomegalovirus cmv vaccine could prevent the majority of birth defects caused by congenital cmv infections. Update on the current status of cytomegalovirus vaccines. The vrppp65 vaccine has entered phase 1 trials in humans, administered in a trivalent formulation with gb and ie1 ul123 vrps. Health care professionals diagnose cmv infections by culturing the virus, detecting cmv dna from the infected individual, or detecting cmv antibodies. Research paper a dnabased vaccine for the prevention of. They find that in contrast to aged individuals where cmv infection decreased response to flu vaccine, cmv infection actually.
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. The eight species in this genus include the type species, human betaherpesvirus 5 hcmv, human cytomegalovirus, hhv5, which is the species that infects humans. A novel therapeutic cytomegalovirus dna vaccine in allogeneic. In the lancet infectious diseases, mohamed kharfandabaja and colleagues describe a phase 2, placebocontrolled trial1 of a therapeutic cytomegalovirus dna vaccine transvax. 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. Rhesus cytomegalovirus rhcmv infection of macaques exhibits strong similarities to human cmv hcmv persistence and pathogenesis. Antiviral treatments may improve the prognosis in some patients with cytomegalovirus infections. March 18, 2009 an experimental vaccine may curb cytomegalovirus in women, which might reduce cmvrelated birth defects in their children thats according to a. 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. Mar 03, 2020 triplex vaccine was developed to enhance cytomegalovirus cmvspecific t cells and prevent cmv reactivation early after hematopoietic stem cell transplant hct. Cmv can cause complications for pregnant people and those with a weakened immune system. 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.
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