Vaccines against Low Molecular Antigens : Novel Strategies and Application - TOBAVAC

Coordinating Institution: Laboratoire National de Santé
Contracting Partner(s): CRP-Santé
Other Partner(s): Faculté de Médecine, Hôpital Erasme (B) , Institut National Polytechnique de Lorraine (F) , Technical University of Munich (Institute of Hydrochemistry and Chemical Balneology) (D) , Université Libre de Bruxelles (B) , University of Louvain (B)
From: 01/06/2002
To: 31/12/2009
Budget: 1,546,503.00€
Contact(s): Müller Claude P.

Summary 2009

The general objective of the TOBAVAC project is to explore a prophylactic immune strategy based on carcinogen-specific antibodies induced by NNK- and B[a]P- hapten conjugates, to lower the risks of chemical carcinogenesis. The First Phase of TOBAVAC (TOBAVAC I) showed that both active and passive specific antibodies protect cells by a number of expected and unexpected mechanisms against adverse effects of carcinogens in vitro.

TOBAVAC I has shown that “pathophysiological” concentrations of NNK and B[a]P can be matched by a 10- to 300-fold molar excess of specific antibodies found after the induction of a specific immune response in vivo. On the basis of these results, we further investigated (TOBAVAC II) how antibodies can influence detrimental biological effects of carcinogens. One of the most important challenges of the TOBAVAC II project was the necessity to use and develop in vivo models based on low concentrations of carcinogens that can be matched by molar excesses of antibody that give measurable, surrogate read-outs in short-term experiments.

Using these surrogate markers, we further improved our immunisation strategy against NNK and B[a]P to generate higher levels of more specific antibodies. Our antibodies did not only bind to NNK but also to NNAL, the two most carcinogenic species of the metabolic cascade. The coupling of B[a]P to T cell epitopes improved the immunogenicity and antibody specificity compared to whole protein conjugates. With both, peptide- and protein based hapten conjugate, we showed also in vivo that an vaccination against B[a]P is absolutely warranted. Antibodies sequestrated B[a]P and its metabolites in the blood stream of mice administrated to low concentrations of B[a]P.

The induction of genes by B[a]P critical for the metabolism of B[a]P was reversed by specific antibodies. These and other effects of B[a]P specific antibodies contribute to a reduced metabolism of B[a]P which may explains a protective effect on B[a]P-induced immunotoxicity and neurotoxicity in vivo. Based on these promising results, the direct effect of specific antibodies on adduct formation and tumourigenesis and on long term protection will be studied in future experiments using transgenic mouse models with higher susceptibility to carcinogens.

Refereed Scientific Publications (only phase II):
  • De Buck SS, Schellenberger MT, Ensch C, Muller CP. Effects of antibodies induced by a conjugate vaccine, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone absorptive transport, metabolism and proliferation of human lung cells. Int J Cancer Epub ahead of print, 2010.
  • MT Schellenberger, N Grova, S Willième, S Farinelle, EJF Prodhomme, CP Muller. Modulation of Benzo[a]pyrene induced immunotoxicity in mice actively immunized with a B[a]P-diphtheria toxoid conjugate. Toxicology & Applied Pharmacology, 240, 37-45, 2009.
  • Grova N, Prodhomme EJ, Schellenberger MT, Farinelle S, Muller CP. Modulation of carcinogen bioavailability by immunisation with benzo[a]pyrene-conjugate vaccines. Vaccine 27:4142-51, 2009
  • Grova N, Schroeder H, Farinelle S, Prodhomme E, Valley A, Muller CP. Sub-acute administration of benzo[a]pyrene (B[a]P) reduces anxiety-related behaviour in adult mice and modulates regional expression of N-methyl-d-aspartate (NMDA) receptors genes in relevant brain regions. Chemosphere 73:S295-302, 2008.
  • Grova N, Valley A, Turner JD, Morel A, Muller CP, Schroeder H. Modulation of behavior and NMDA-R1 gene mRNA expression in adult female mice after sub-acute administration of benzo(a)pyrene. Neurotoxicology 28:630-6, 2007.
Project Website:

Figure: Stéphanie WILLIEME, Claude P. MULLER, Mario SCHELLENBERGER, Sophie FARINELLE (left to right)