title: Modification of Ad5 hexon hypervariable regions circumvents pre-existing Ad5 neutralizing antibodies and induces protective immune responses.
abstract: The development of an effective malaria vaccine is a high global health priority. Vaccine vectors based on adenovirus type 5 are capable of generating robust and protective T cell and antibody responses in animal models and are currently being evaluated in clinical trials for HIV and malaria. They appear to be more effective in terms of inducing antigen-specific immune responses as compared with non-Ad5 serotype vectors. However, the high prevalence of neutralizing antibodies to Ad5 in the human population, particularly in the developing world, has the potential to limit the effectiveness of Ad5-based vaccines. We have generated novel Ad5-based vectors that precisely replace the hexon hypervariable regions with those derived from Ad43, a subgroup D serotype with low prevalence of neutralizing antibody in humans. We have demonstrated that these hexon-modified adenovectors are not neutralized efficiently by Ad5 neutralizing antibodies in vitro using sera from mice, rabbits and human volunteers. We have also generated hexon-modified adenovectors that express a rodent malaria parasite antigen, PyCSP, and demonstrated that they are as immunogenic as an unmodified vector. Furthermore, in contrast to the unmodified vector, the hexon-modified adenovectors induced robust T cell responses in mice with high levels of Ad5 neutralizing antibody. We also show that the hexon-modified vector can be combined with unmodified Ad5 vector in prime-boost regimens to induce protective responses in mice. Our data establish that these hexon-modified vectors are highly immunogenic even in the presence of pre-existing anti-adenovirus antibodies. These hexon-modified adenovectors may have advantages in sub-Saharan Africa where there is a high prevalence of Ad5 neutralizing antibody in the population.
authors.affiliation: Research, GenVec, Inc., Gaithersburg, Maryland, United States of America. jbruder@genvec.com
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Bruder
authors.forename: Elena
authors.initials: E
authors.lastname: Semenova
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Keith
authors.initials: K
authors.lastname: Limbach
authors.forename: Noelle B
authors.initials: NB
authors.lastname: Patterson
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Stefaniak
authors.forename: Svetlana
authors.initials: S
authors.lastname: Konovalova
authors.forename: Charlie
authors.initials: C
authors.lastname: Thomas
authors.forename: Melissa
authors.initials: M
authors.lastname: Hamilton
authors.forename: C Richter
authors.initials: CR
authors.lastname: King
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Richie
authors.forename: Denise L
authors.initials: DL
authors.lastname: Doolan
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D011817:Rabbits; D013601:T-Lymphocytes / Q000276:immunology; D019076:Transgenes / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D036022:Capsid Proteins; D014765:Viral Vaccines; C018315:hexon capsid protein, Adenovirus