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9/26/2014  |   4:30 PM - 6:00 PM   |  

A Vaxfectin®-formulated DNA Vaccine Induces Antibodies that Block Cytomegalovirus Entry into Fibroblasts and Epithelial Cells

A vaccine to prevent congenital cytomegalovirus (CMV) infections is an international priority. Investigational vaccines have targeted the viral glycoprotein B (gB) as an inducer of neutralizing antibodies and phosphoprotein 65 (pp65) as an inducer of cytotoxic T cells. However, while antibodies to gB neutralize CMV entry into all cell types, their potency is low compared to antibodies that block epithelial and endothelial cell entry through targeting the pentameric complex (PC). Hence, more potent neutralizing responses might be obtained using a vaccine that combines gB with PC-derived antigens. To assess the ability of PC subunits to induce neutralizing antibodies, DNA vaccines encoding PC subunits UL128, UL130, or UL131 were constructed and formulated with Vaxfectin®, an adjuvant that enhances antibody responses induced by DNA. Mice were immunized with the three individual DNA vaccines or with pair-wise or trivalent combinations. Only the UL130 vaccine induced epithelial neutralizing antibodies and no synergy was observed from pair-wise or trivalent combinations. Individual vaccines were next evaluated in rabbits, and again only the UL130 vaccine induced epithelial neutralizing antibodies. To determine if the UL130 vaccine synergizes or antagonizes DNA vaccines encoding gB or pp65, mono-, bi-, or tri-valent combinations were evaluated in rabbits. Fibroblast and epithelial neutralizing titers did not differ between rabbits immunized with gB alone vs. gB/UL130, gB/pp65, or gB/UL130/pp65 combinations. Thus, while there was no antagonism from coadministration of DNA vaccines, there was also no synergy. Importantly, gB-induced epithelial neutralizing titers were substantially (43-fold) higher than activities induced by UL130, and both fibroblast and epithelial neutralizing titers induced by either the gB/pp65 or gB/UL130/pp65 combinations were comparable to those observed in humans with naturally-acquired CMV infections. These findings support further development of Vaxfectin®-formulated bivalent gB/pp65 or trivalent UL130/gB/pp65 DNA vaccines for prevention of congenital CMV infections.

Michael McVoy (Point of Contact,Primary Presenter,Author), mmcvoy@vcu.edu;
Dr. McVoy received a BS in Biology and Chemistry from the College of William and Mary, Williamsburg Virginia, USA in 1983 and a PhD in Microbiology & Immunology from Virginia Commonwealth University, Richmond Virginia, USA in 1993. As a post-doctoral fellow with Dr. Edward Mocarski at Stanford University, his research focused on CMV DNA packaging. In 1995 Dr. McVoy returned to Virginia Commonwealth University as an Assistant Professor in the Department of Pediatrics. He was promoted to Associate Professor with tenure in 2002 and full Professor in 2006. His early research focused on basic mechanisms of herpesvirus DNA replication and packaging with a goal of facilitating development of new antiherpesviral drugs. More recently his research has contributed toward development of the guinea pig cytomegalovirus model of congenital infection and the application of emerging progress in CMV molecular biology to the design and evaluation of novel CMV vaccines.

ASHA DISCLOSURE:

Financial - No relevant financial relationship exist.

Nonfinancial - No relevant nonfinancial relationship exist.

Ronzo Lee (Author), rlee3@mcvh-vcu.edu;
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Jukka Hartikka (Author), hartikkajukka@gmail.com;
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Larry Smith (Author), LSmith@vical.com;
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Frances Saccoccio (Author), francessac@gmail.com;
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Jian Ben Wang (Author), jbwang@vcu.edu;
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Xiaohong Cui (Author), xcui@vcu.edu;
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Stuart Adler (Author), sadler@vcu.edu;
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