Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector

Schleiss, Mark R.; Berka, Ursula; Watson, Elizabeth M.; Aistleithner, Mario; Kiefmann, Bettina; Mangeat, Bastien; Swanson, Elizabeth C.; Gillis, Peter A.; Hernandez-Alvarado, Nelmary; Fernández-Alarcón, Claudia; Zabeli, Jason C.; Pinschewer, Daniel D.; Lilja, Anders; Schwendinger, Michael G.; Guirakhoo, Farshad; Monath, Thomas P.; Orlinger, Klaus K.

doi:10.1128/cvi.00300-16

Cited by 32 publications

(24 citation statements)

References 45 publications

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“…Despite the ill-defined protection by natural HCMV immunity, both humoral and cellular immune responses have been implicated in controlling HCMV infection (30,31). Clinical and surrogate animal studies indicate that the prevention of congenital HCMV infection involves antibodies to different envelope glycoprotein complexes, including gB, gH/gL, and the PC as well as T cells to immunodominant antigens such as phosphoprotein 65 (pp65) (32)(33)(34)(35)(36)(37)(38)(39). High-titer NAb, PC-specific NAb, and pp65-specific CD4 ϩ T cells have been associated with reduced risk of intrauterine virus transmission following primary maternal HCMV infection (33,36,(39)(40)(41).…”

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confidence: 99%

Multiantigenic Modified Vaccinia Virus Ankara Vaccine Vectors To Elicit Potent Humoral and Cellular Immune Reponses against Human Cytomegalovirus in Mice

Chiuppesi

Nguyen

Park

et al. 2018

J Virol

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As human cytomegalovirus (HCMV) is a common cause of disease in newborns and transplant recipients, developing an HCMV vaccine is considered a major public health priority. Yet an HCMV vaccine candidate remains elusive. Although the precise HCMV immune correlates of protection are unclear, both humoral and cellular immune responses have been implicated in protection against HCMV infection and disease. Here we describe a vaccine approach based on the well-characterized modified vaccinia virus Ankara (MVA) vector to stimulate robust HCMV humoral and cellular immune responses by an antigen combination composed of the envelope pentamer complex (PC), glycoprotein B (gB), and phosphoprotein 65 (pp65). We show that in mice, multiantigenic MVA vaccine vectors simultaneously expressing all five PC subunits, gB, and pp65 elicit potent complement-independent and complement-dependent HCMV neutralizing antibodies as well as mouse and human MHC-restricted, polyfunctional T cell responses by the individual antigens. In addition, we demonstrate that the PC/gB antigen combination of these multiantigenic MVA vectors can enhance the stimulation of humoral immune responses that mediate neutralization of different HCMV strains and antibody-dependent cellular cytotoxicity. These results support the use of MVA to develop a multiantigenic vaccine candidate for controlling HCMV infection and disease in different target populations, such as pregnant women and transplant recipients. The development of a human cytomegalovirus (HCMV) vaccine to prevent congenital disease and transplantation-related complications is an unmet medical need. While many HCMV vaccine candidates have been developed, partial success in preventing or controlling HCMV infection in women of childbearing age and transplant recipients has been observed with an approach based on envelope glycoprotein B (gB). We introduce a novel vaccine strategy based on the clinically deployable modified vaccinia virus Ankara (MVA) vaccine vector to elicit potent humoral and cellular immune responses by multiple immunodominant HCMV antigens, including gB, phosphoprotein 65, and all five subunits of the pentamer complex. These findings could contribute to development of a multiantigenic vaccine strategy that may afford more protection against HCMV infection and disease than a vaccine approach employing solely gB.

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confidence: 99%

Multiantigenic Modified Vaccinia Virus Ankara Vaccine Vectors To Elicit Potent Humoral and Cellular Immune Reponses against Human Cytomegalovirus in Mice

Chiuppesi

Nguyen

Park

et al. 2018

J Virol

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“…This feature might be highly desirable for sustaining protection (conferred by periodic booster immunizations) against congenital CMV in women of reproductive age during serial pregnancies. The utility of this approach was recently demonstrated in the GPCMV model of congenital infection (63,64), providing support for evaluation of these vectors in human clinical trials. This platform was developed by Hookipa Biotech AG.…”

Section: Vectored CMV Vaccinesmentioning

confidence: 90%

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

Schleiss

Permar

Plotkin

2017

Clin Vaccine Immunol

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A vaccine against congenital human cytomegalovirus (CMV) infection is a major public health priority. Congenital CMV causes substantial long-term morbidity, particularly sensorineural hearing loss (SNHL), in newborns, and the public health impact of this infection on maternal and child health is underrecognized. Although progress toward development of a vaccine has been limited by an incomplete understanding of the correlates of protective immunity for the fetus, knowledge about some of the key components of the maternal immune response necessary for preventing transplacental transmission is accumulating. Moreover, although there have been concerns raised about observations indicating that maternal seropositivity does not fully prevent recurrent maternal CMV infections during pregnancy, it is becoming increasing clear that preconception immunity does confer some measure of protection against both CMV transmission and CMV disease (if transmission occurs) in the newborn infant. Although the immunity to CMV conferred by both infection and vaccination is imperfect, there are encouraging data emerging from clinical trials demonstrating the immunogenicity and potential efficacy of candidate CMV vaccines. In the face of the knowledge that between 20,000 and 30,000 infants are born with congenital CMV in the United States every year, there is an urgent and compelling need to accelerate the pace of vaccine trials. In this minireview, we summarize the status of CMV vaccines in clinical trials and provide a perspective on what would be required for a CMV immunization program to become incorporated into clinical practice.

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“…Several different viral vectors have been used for HCMV vaccine development, and modified vaccinia virus Ankara (MVA) vector vaccine candidates demonstrated the most promising results. [96][97][98][99][100][101][102][103][104][105] MVA is one of the most advanced viral vectors for vaccine development and clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant antigens. 106 MVA has been used to express a variety of HCMV antigens, including pp65, gB, IE1, IE2, and the pentameric complex proteins.…”

Section: Viral Vector Hcmv Vaccinesmentioning

confidence: 99%

“…Multi-antigen vaccine candidates for HCMV using the combination of gB and pp65, either as DNA or co-expressed in a viral vector, were highly immunogenic and demonstrated additive protection in a guinea pig congenital transmission model. 61,105 Live attenuated vaccines are unlikely to provide protection that exceeds the level of natural immunity, and the efficacy of viral vector vaccines could be significantly reduced by vector-specific immune response elicited after repeated immunization. The use of a combination of HCMV recombinant proteins such as trimeric gB and the pentameric complex represents a safe and efficient approach that could potentially provide superior protection over natural immunity.…”

Section: Rna Hcmv Vaccinesmentioning

confidence: 99%

Development of novel vaccines against human cytomegalovirus

Cui

Snapper

2019

Human Vaccines & Immunotherapeutics

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Congenital human cytomegalovirus (HCMV) infection and HCMV infection of the immunosuppressed patients cause significant morbidity and mortality, and vaccine development against HCMV is a major public health priority. Efforts to develop HCMV vaccines have been ongoing for 50 y, though no HCMV vaccine has been licensed; encouraging and promising results have obtained from both preclinical and clinical trials. HCMV infection induces a wide range of humoral and T cell-mediated immune responses, and both branches of immunity are correlated with protection. In recent years, there have been novel approaches toward the development of HCMV vaccines and demonstrated that vaccine candidates could potentially provide superior protection over natural immunity acquired following HCMV infection. Further, rationally designed HCMV protein antigens that express native conformational epitopes could elicit optimal immune response. HCMV vaccine candidates, using a multi-antigen approach, to maximize the elicited protective immunity will most likely be successful in development of HCMV vaccine.

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Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector

Cited by 32 publications

References 45 publications

Multiantigenic Modified Vaccinia Virus Ankara Vaccine Vectors To Elicit Potent Humoral and Cellular Immune Reponses against Human Cytomegalovirus in Mice

Multiantigenic Modified Vaccinia Virus Ankara Vaccine Vectors To Elicit Potent Humoral and Cellular Immune Reponses against Human Cytomegalovirus in Mice

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

Development of novel vaccines against human cytomegalovirus

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