Modification of Ad5 hexon hypervariable regions circumvents pre-existing Ad5 neutralizing antibodies and induces protective immune responses

PLoS One. 2012;7(4):e33920. doi: 10.1371/journal.pone.0033920. Epub 2012 Apr 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / immunology*
  • Animals
  • Antibodies, Neutralizing / immunology*
  • Capsid Proteins / genetics
  • Capsid Proteins / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Engineering
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology*
  • Humans
  • Immunity, Cellular / immunology*
  • Immunization
  • Mice
  • Mice, Inbred BALB C
  • Neutralization Tests
  • Rabbits
  • T-Lymphocytes / immunology
  • Transgenes / immunology
  • Viral Vaccines / administration & dosage
  • Viral Vaccines / immunology*

Substances

  • Antibodies, Neutralizing
  • Capsid Proteins
  • Viral Vaccines
  • hexon capsid protein, Adenovirus