Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine that selectively elicits potent neutralizing antibodies

Anna Kabanova, Laurent Perez, Daniele Lilleri, Jessica Marcandalli, Gloria Agatic, Simone Becattini, Silvia Preite, Dario Fuschillo, Elena Percivalle, Federica Sallusto, Giuseppe Gerna, Davide Corti, Antonio Lanzavecchia

Research output: Contribution to journalArticlepeer-review

Abstract

The use of neutralizing antibodies to identify the most effective antigen has been proposed as a strategy to design vaccines capable of eliciting protective B-cell immunity. In this study, we analyzed the human antibody response to cytomegalovirus (human cytomegalovirus, HCMV) infection and found that antibodies to glycoprotein (g)B, a surface glycoprotein that has been developed as a HCMV vaccine, were primarily nonneutralizing. In contrast, most of the antibodies to the complex formed by gH, gL, protein (p)UL128, pUL130, and pUL131 (the gHgLpUL128L pentamer) neutralized HCMV infection with high potency. Based on this analysis, we developed a single polycistronic vector encoding the five pentamer genes separated by "self-cleaving" 2A peptides to generate a stably transfected CHO cell line constitutively secreting high levels of recombinant pentamer that displayed the functional antigenic sites targeted by human neutralizing antibodies. Immunization of mice with the pentamer formulated with different adjuvants elicited HCMV neutralizing antibody titers that persisted to high levels over time and that were a hundred- to thousand-fold higher than those found in individuals that recovered from primary HCMV infection. Sera from mice immunized with the pentamer vaccine neutralized infection of both epithelial cells and fibroblasts and prevented cell-to-cell spread and viral dissemination from endothelial cells to leukocytes. Neutralizing monoclonal antibodies from immunized mice showed the same potency as human antibodies and targeted the same as well as additional sites on the pentamer. These results illustrate with a relevant example a general and practical approach of analytic vaccinology for the development of subunit vaccines against complex pathogens.

Original languageEnglish
Pages (from-to)17965-17970
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number50
DOIs
Publication statusPublished - Dec 16 2014

Keywords

  • Analytic vaccinology
  • Human cytomegalovirus
  • Vaccine

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine that selectively elicits potent neutralizing antibodies'. Together they form a unique fingerprint.

Cite this