Preclinical evaluation of innate immunity to baculovirus gene therapy vectors in whole human blood

Mol Immunol. 2009 Sep;46(15):2911-7. doi: 10.1016/j.molimm.2009.07.008. Epub 2009 Aug 8.


Interactions of gene therapy vectors with human blood components upon intravenous administration have a significant effect on vector efficacy and patient safety. Here we describe methods to evaluate these interactions and their effects in whole human blood, using baculovirus vectors as a model. Opsonisation of baculovirus particles by binding of IgM and C3b was demonstrated, which is likely to be the cause of the significant blood cell-associated virus that was detected. Preventing formation of the complement C5b-9 (membrane attack) complex maintained infectivity of baculovirus particles as shown by studying the effects of two specific complement inhibitors, Compstatin and a C5a receptor antagonist. Formation of macroscopic blood clots after 4h was prevented by both complement inhibitors. Pro- and anti-inflammatory cytokines Il-1beta, IL-6, IL-8 and TNF-alpha were produced at variable levels between volunteers and complement inhibitors showed patient-specific effects on cytokine levels. Whilst both complement inhibitors could play a role in protecting patients from aggressive inflammatory reactions, only Compstatin maintained virus infectivity. We conclude that this ex vivo model, used here for the first time with infectious agents, is a valuable tool in evaluating human innate immune responses to gene therapy vectors or to predict the response of individual patients as part of a clinical trial or treatment. The use of complement inhibitors for therapeutic viruses should be considered on a patient-specific basis.

Publication types

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

MeSH terms

  • Baculoviridae / genetics
  • Baculoviridae / immunology*
  • Complement C3b / immunology
  • Complement C5a / pharmacology
  • Complement Membrane Attack Complex / drug effects
  • Complement Membrane Attack Complex / immunology*
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Genetic Therapy*
  • Genetic Vectors / blood*
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology*
  • Humans
  • Immunity, Innate* / drug effects
  • Immunoassay
  • Immunoglobulin M / blood
  • Peptides, Cyclic / pharmacology


  • C5aRAD
  • Complement Membrane Attack Complex
  • Cytokines
  • Immunoglobulin M
  • Peptides, Cyclic
  • compstatin
  • Complement C3b
  • Complement C5a