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Session 88 Poster Abstracts
Construction and Evaluation of Vaccine Strategies
Wednesday, 1:30 - 3:30 pm
Hall D


491    
Functionally Significant Adenovirus Serotype 5 Neutralizing Antibodies Are Directed Primarily Against the Adenovirus Hexon Protein
Shawn Sumida*1, D Truitt1, A Lemckert2, R Vogels2, J Custers2, M Addo3, S Lockman4, T Peter4, F Peyerl1, S Jackson1, M Essex4, B Walker3, J Goudsmit2, M Havenga2, and D Barouch1
1Beth Israel Deaconess Med Ctr and Harvard Med Sch, Boston, MA, USA; 2Crucell, Leiden, The Netherlands; 3Partners AIDS Res Ctr, Massachusetts Gen Hosp, Harvard Med Sch, Charlestown, USA; and 4Harvard Sch of Publ Hlth, Boston, MA, USA

Background:  The utility of recombinant adenovirus serotype 5 (ADV5) vector-based vaccines for HIV-1 and other pathogens will likely be substantially limited by the high sero prevalence of ADV5-specific neutralizing antibodies (Nab) in human populations. However, the primary targets of ADV5-specific Nab remain poorly characterized. Here we utilize capsid chimeric viruses to assess the titers and functional significance of Nab directed against the major ADV5 capsid proteins.

Methods:  ADV5-specific Nab responses were assessed in serum samples by luciferase-based virus neutralization assays. To study the functional importance of ADV5-specific Nab, IgG was first purified from serum from mice that were pre-immunized with capsid chimeric ADV5/ADV35 vectors and then adoptively transferred to naive recipient mice prior to vaccination with rAVD5-Env. Vaccine-elicited immune responses were assessed by tetramer, ELISpot, and ELISA assays. Comparisons of immune responses among groups were performed by analyses of variance.

Results:  Virus neutralization assays utilizing serum samples from humans and immunized mice demonstrated that ADV5-specific Nab were directed against both the hexon and fiber proteins, but hexon-specific Nab titers were typically 5- to 10-fold higher than fiber-specific Nab titers. Adoptive transfer studies were then performed to evaluate the capacity of hexon- and fiber-specific Nab to suppress the immunogenicity of a rADV5-Env vaccine in mice. Importantly, hexon-specific Nabs were remarkably efficient at suppressing rADV5 vaccine-elicited immune responses. In contrast, even high titers of fiber-specific Nabs exerted minimal to no suppressive effects on rADV5 vaccine immunogenicity.

Conclusions:  These data demonstrate that functionally significant ADV5-specific Nab are directed primarily against the ADV5 hexon protein. Moreover, these studies suggest a potential strategy for engineering novel ADV5 vectors to evade dominant ADV5-specific Nab.

Keywords: Adenovirus Serotype 5; Neutralizing Antibodies; Pre-existing Immunity