The potently neutralizing monoclonal antibody 1B7 : its unique epitope, effects on intracellular trafficking, and elicitation upon infection with pertussis

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Title: The potently neutralizing monoclonal antibody 1B7 : its unique epitope, effects on intracellular trafficking, and elicitation upon infection with pertussis
Author: Sutherland, Jamie Nicole
Abstract: Disease caused by Bordetella pertussis persists with rates increasing over the past decade in industrialized countries . A hindrance to vaccine development has been the lack of a clear serological correlate of protective immunity . Pertussis toxin (PTx ) , an AB -type toxin , is one of the bacteria’s major virulence factors and among the lead candidates for potential correlates . Of the numerous monoclonal antibodies (mAbs ) binding PTx , the murine IgG2a mAb 1B7 is potently neutralizing in all in vitro assays and in vivo murine models of infection . 1B7 binds an epitope on the enzymatic S1 -subunit of PTx with some linear elements but previous work was unable to more precisely define the epitope or determine its exact mechanism of protection . We characterize the epitope bound by 1B7 on PTx -S1 in molecular detail and define energetically important interactions between residues at the interface including six residues on PTx -S1 and six residues on 1B7 . Using this information , a model of the 1B7 -S1 interaction was developed , indicating a predominantly conformational epitope located on the base of S1 near S4 . The location of this epitope is consistent with previous data and is shown to be conserved across several naturally occurring strain variants including PTx -S1A , B , D , and E in addition to the catalytically inactive 9K /129G variant . Using immunofluorescent microscopy , it was determined that 1B7’s unique mode of action lies in its ability to bind to the toxin and co -traffic into target cells . Upon endocytosis , 1B7 protects from PTx intoxication by redirecting its intracellular retrograde trafficking . In order to determine whether antibody responses are differently induced by infection or acellular vaccination , we analyzed sera from 30 adults with confirmed exposure to pertussis and 30 recent vaccinees . Natural infection resulted in significantly higher titers of anti -PTx -S1 , 1B7 -like , and 11E6 -like antibodies , while overall anti -PTx titers were similar to vaccinated samples . We also observed a direct correlation between in vitro protection and the presence of 1B7 -like and 11E6 -like antibodies . Thus , natural infection elicits higher titers of protective antibodies indicating that the use of detoxified PTx in current acellular vaccines although highly immunogenic results in the elicitation of predominantly non -neutralizing antibodies .
URI: http : / /hdl .handle .net /2152 /ETD -UT -2010 -08 -1870
Date: 2010-12-07

Citation

The potently neutralizing monoclonal antibody 1B7 : its unique epitope, effects on intracellular trafficking, and elicitation upon infection with pertussis. Doctoral dissertation, University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /ETD -UT -2010 -08 -1870 .

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