Title |
Modification of Ad5 Hexon Hypervariable Regions Circumvents Pre-Existing Ad5 Neutralizing Antibodies and Induces Protective Immune Responses
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Published in |
PLOS ONE, April 2012
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DOI | 10.1371/journal.pone.0033920 |
Pubmed ID | |
Authors |
Joseph T. Bruder, Elena Semenova, Ping Chen, Keith Limbach, Noelle B. Patterson, Maureen E. Stefaniak, Svetlana Konovalova, Charlie Thomas, Melissa Hamilton, C. Richter King, Thomas L. Richie, Denise L. Doolan |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 56 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 14 | 25% |
Student > Ph. D. Student | 12 | 21% |
Student > Master | 10 | 18% |
Other | 3 | 5% |
Professor | 2 | 4% |
Other | 5 | 9% |
Unknown | 10 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 12 | 21% |
Biochemistry, Genetics and Molecular Biology | 10 | 18% |
Medicine and Dentistry | 6 | 11% |
Immunology and Microbiology | 5 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 5% |
Other | 5 | 9% |
Unknown | 15 | 27% |