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9/27/2014  |   10:00 AM - 10:30 AM   |  Ballroom A

Antibody-Driven Vaccine Design: Identification of the Human Cytomegalovirus gHgLpUL128L Complex as a Subunit Vaccine.

Considerable efforts have been made in the last decade to develop vaccines capable of preventing HCMV infection. The abundant virion protein gB represents the basis of most vaccines developed so far. However, in recent phase II trials, a MF59-adjuvanted gB vaccine showed only a 50% efficacy in preventing infection of seronegative women. In this study, we used the information gained from the analysis of the human neutralizing antibody response to HCMV infection to identify the pentameric complex formed by gH, gL, pUL128, pUL130, and pUL131 (gHgLpUL128L) as the most suitable HCMV vaccine candidate. We observed that the serum neutralizing activity against HCMV is mainly directed against the gHgLpUL128L pentameric complex. Human monoclonal antibodies isolated from memory B cells of immune donors that bind to conformational epitopes of gHgLpUL128L were extraordinarily potent in neutralizing HCMV infection of epithelial, endothelial and myeloid cells, as well as in blocking cell-to-cell virus spreading, when compared to monoclonal antibodies directed to gB. Moreover, while the great majority of antibodies binding to gHgLpUL128L have a neutralizing activity, the majority of anribodies binding to gB are non-neutralizing. Finally, we observed that development of an early antibody response to the pentamer was associated with a reduced risk of HCMV transmission to the fetus. Thus, a soluble complex of the five glycoproteins was produced in mammalian cells and found to display all the functional antigenic sites targeted by a large panel of human neutralizing monoclonal antibodies. Immunization of mice with gHgLpUL128L with different adjuvants elicited a significantly stronger antibody response compared to soluble gB, both for virus neutralizing activity, protection of different cellular targets, and inhibition of virus spreading. These results indicate that the HCMV gHgLpUL128L pentamer is a strong candidate for a vaccine capable of selectively inducing a broad and potent protective antibody response.

Daniele Lilleri (Point of Contact,Primary Presenter,Author), d.lilleri@smatteo.pv.it;
1998-2003: specialization at “Servizio di Virologia, Fondazione IRCCS Policlinico San Matteo”. 2003-2010: research contract at “Servizio di Virologia, Fondazione IRCCS Policlinico San Matteo” 2010-present: reserch contract at “Laboratori Sperimentali di Ricerca, Fondazione IRCCS Policlinico San Matteo” and Visiting Scientist at Institute for Research in Biomedicine, Bellinzona, Switzerland Research activity: -validation of new molecular assays for diagnosis and monitoring of human cytomegalovirus (HCMV) infections in immunocompetent and immunocompromised subjects; -analysis of HCMV-specific humoral and cell-mediated immune responses in immunocompetent and immunocompromised subjects; -identification of the main pathogenetic features of HCMV infection.

ASHA DISCLOSURE:

Financial - No relevant financial relationship exist.

Nonfinancial - No relevant nonfinancial relationship exist.

Anna Kabanova (Author), anna.kabanova@unisi.it;
post-doc at IRB, Bellinzona, Switzerland, from 2010 to 2013, now at University of Siena, Italy

Laurent Perez (Author), laurent.perez@irb.usi.ch;
Responsible of the protein production facility, IRB, Bellinzona, Switzerland

Federica Sallusto (Author), federica.sallusto@irb.usi.ch;
Group Leader of the Cellular Immunology Group at IRB, Bellinzona, Switzerland.

Giuseppe Gerna (Author), g.gerna@smatteo.pv.it;
Former director of Viral Diagnostic Service, now Scientist at Experimental Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Davide Corti (Author), davide.corti@humabs.ch;
Senior Scientist at IRB, Bellinzona and CSO at Humabs, Bellinzona, Switzerland

Antonio Lanzavecchia (Author), lanzavecchia@irb.usi.ch;
Group leader of Immune Regulation Group and Director of IRB, Bellinzona, Switzerland

Presentation:
301DanieleLilleri.pdf

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