Development of a vaccine against cytomegalovirus infection and disease

Luisi, Kate; Sharma, Madhu; Yü, Dong

doi:10.1016/j.coviro.2017.02.003

Cited by 10 publications

(6 citation statements)

References 70 publications

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“…Several vaccine candidates are currently being tested in pre-clinical or clinical studies (reviewed in [9]). However, there is still an ongoing debate with regard to the goals and the appropriate formulations of a vaccine (reviewed in [9,10,11,12,13,14]). The tegument protein pp65 (pUL83) and the immediate-early protein 1 (IE1, pUL123) have gained broad endorsement as being major T lymphocyte antigens to be included in a vaccine.…”

Section: Introductionmentioning

confidence: 99%

Production Strategies for Pentamer-Positive Subviral Dense Bodies as a Safe Human Cytomegalovirus Vaccine

et al. 2019

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Infections with the human cytomegalovirus (HCMV) are associated with severe clinical manifestations in children following prenatal transmission and after viral reactivation in immunosuppressed individuals. The development of an HCMV vaccine has long been requested but there is still no licensed product available. Subviral dense bodies (DB) are immunogenic in pre-clinical models and are thus a promising HCMV vaccine candidate. Recently, we established a virus based on the laboratory strain Towne that synthesizes large numbers of DB containing the pentameric protein complex gH/gL/UL128-131 (Towne-UL130repΔGFP). The work presented here focuses on providing strategies for the production of a safe vaccine based on that strain. A GMP-compliant protocol for DB production was established. Furthermore, the DB producer strain Towne-UL130rep was attenuated by deleting the UL25 open reading frame. Additional genetic modifications aim to abrogate its capacity to replicate in vivo by conditionally expressing pUL51 using the Shield-1/FKBP destabilization system. We further show that the terminase inhibitor letermovir can be used to reduce infectious virus contamination of a DB vaccine by more than two orders of magnitude. Taken together, strategies are provided here that allow for the production of a safe and immunogenic DB vaccine for clinical testing.

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Section: Introductionmentioning

confidence: 99%

Production Strategies for Pentamer-Positive Subviral Dense Bodies as a Safe Human Cytomegalovirus Vaccine

et al. 2019

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“…36 Currently, there is no CMV vaccine available, although vaccine trials are in progress. 37 5 | HOW CAN YOU PREVENT MATERNAL-FETAL CMV TRANSMISSION? 5.1 | Expectant mother: "If I have CMV infection in pregnancy how can I prevent it being transmitted to my unborn baby?…”

Section: How Does CMV Infection Maternal-fetal Transmission and Fmentioning

confidence: 99%

Fetal therapies for cytomegalovirus: What we tell prospective parents

et al. 2020

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Congenital CMV is the most common congenital infection in the developed world. Infection results in congenital disease ranging from asymptomatic infection to severe neurodevelopmental impairment, and occasionally fetal or neonatal death. Fetal infection can occur through maternal-fetal transmission during primary maternal infection or maternal reactivation or re-infection. Awareness among maternal health care providers and parents is low. The prevention of maternal CMV infection currently relies on hygiene measures, with no effective CMV vaccine or prophylactic therapies. No licensed treatment options are available to prevent maternal-fetal transmission or fetal disease. Hyperimmunoglobulin and valaciclovir have been investigated for prevention of maternal-fetal transmission or fetal treatment, with some evidence supporting consideration of maternal administration of hyperimmunoglobulin or valaciclovir therapy in certain circumstances. This article outlines the clinical evidence regarding proven preventative behavioral measures and experimental hyperimmunoglobulin and valaciclovir therapies, that is structured around common questions asked by pregnant women about CMV infection. It is aimed to help maternity health care providers counsel prospective parents about congenital CMV disease and the preventative and therapeutic strategies currently available. 1 | INTRODUCTION Congenital CMV infection remains a predominant infectious cause of lifelong disability, as well as a cause of stillbirth and neonatal mortality. It is estimated that 1 in 150 infants are born with congenital CMV infection, making it the commonest congenital infection in the developed world. 1,2 Congenital CMV can occur through primary infection in seronegative pregnant women or through CMV reactivation or re-infection in seropositive pregnant women. 3 However, the likelihood of maternal-fetal transmission of CMV is much higher for primary maternal infection (32%) compared with recurrent maternal infection (1.4%). 1 In addition, first trimester infection is also associated with increased rates of adverse neonatal/infant outcomes compared with infection later in pregnancy (20%-45% vs 6%-17%). 4 Overall, when a mother has primary CMV in the first trimester, it is estimated that 1 in 10 fetuses or neonates will have an adverse perinatal outcome. 4 This may involve sensorineural hearing loss (SNHL), chorioretinitis, microcephaly, hepatomegaly, jaundice, thrombocytopenia, neurodevelopmental impairment, stillbirth, or neonatal death. Of those with symptomatic congenital CMV at birth, approximately one in two infants will have permanent sequelae, chiefly SNHL or

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“…Particularly challenging for the development of CMV vaccines are the needs to prevent primary infection, reinfection, and reactivation at the same time as overcoming the capacity of the virus to generate highly sophisticated immunomodulatory mechanisms [81]. Historically, the first CMV vaccines were developed during the 1970s and were based on attenuated virus strains AD-169 and Towne; however, over time a multiplicity of vaccine candidates have been developed [82]. Several live virus vaccines have been evaluated, comprehensively reviewed by Gerna and Lilleri [83], in which various approaches (e.g., genetically modified V160 vaccine, Towne/Toledo recombinant chimera vaccines, viral vectored vaccines, and Alphavirus replicon particles vaccines) have been used to achieve satisfactory immunogenicity and safety profiles.…”

Section: Congenital Cytomegalovirus Infection and Hearing Lossmentioning

confidence: 99%

Cytomegalovirus and Epstein–Barr Virus Associations with Neurological Diseases and the Need for Vaccine Development

Maple

2020

Vaccines

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Herpesviruses have been isolated from a wide range of hosts including humans—for which, nine species have been designated. The human herpesviruses are highly host adapted and possess the capacity for latency, allowing them to survive in the host for life, effectively hidden from the immune system. This ability of human herpesviruses to modulate the host immune response poses particular challenges for vaccine development but at the same time proves attractive for the application of human herpesvirus vaccines to certain spheres of medicine. In this review, congenital cytomegalovirus (CMV) infection and hearing loss will be described followed by a comment on the status of current vaccine development. Secondly, the association of Epstein–Barr virus (EBV) infection with multiple sclerosis (MS) and how EBV vaccination may be of benefit will then be discussed. Prevention of congenital CMV by vaccination is an attractive proposition and several vaccines have been evaluated for potential use. Particularly challenging for the development of CMV vaccines are the needs to prevent primary infection, reinfection, and reactivation at the same time as overcoming the capacity of the virus to generate highly sophisticated immunomodulatory mechanisms. Cost and the practicalities of administering potential vaccines are also significant issues, particularly for low- and middle-income countries, where the burden of disease is greatest. An effective EBV vaccine that could prevent the 200,000 new EBV-associated malignancies which occur globally each year is not currently available. There is increasing interest in developing EBV vaccines to prevent MS and, in view of the association of infectious mononucleosis with MS, reducing childhood infectious mononucleosis is a potential intervention. Currently, there is no licensed EBV vaccine and, in order to progress the development of EBV vaccines for preventing MS, a greater understanding of the association of EBV with MS is required.

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Development of a vaccine against cytomegalovirus infection and disease

Cited by 10 publications

References 70 publications

Production Strategies for Pentamer-Positive Subviral Dense Bodies as a Safe Human Cytomegalovirus Vaccine

Production Strategies for Pentamer-Positive Subviral Dense Bodies as a Safe Human Cytomegalovirus Vaccine

Fetal therapies for cytomegalovirus: What we tell prospective parents

Cytomegalovirus and Epstein–Barr Virus Associations with Neurological Diseases and the Need for Vaccine Development

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