title: Limitations of in vivo IL-12 supplementation strategies to induce Th1 early life responses to model viral and bacterial vaccine antigens.
abstract: The limited induction of Th1 and cytotoxic immune responses is regarded as the main reason for the increased susceptibility to intracellular microorganisms in early life. Recently, in vitro IL-12 supplementation was shown to enhance the limited IFN-gamma release of measles-specific infant T cells. Using a series of IL-12 delivery systems, we show here that in vivo IL-12 supplementation may enhance early life murine Th1 responses to two model vaccine antigens, measles virus hemagglutinin and tetanus toxin peptide. However, this required multiple repeat injections of recombinant rIL-12, which were poorly tolerated in young mice. Local IL-12 delivery by an IL-12 expressing canarypox vector proved safe but failed to modulate vaccine responses. An IL-12 DNA plasmid or a CD40L DNA plasmid efficiently enhanced neonatal Th1 responses to measles hemagglutinin DNA vaccine. However, both plasmids only enhanced Th1 responses to DNA and not to peptide, protein, or live viral vaccines. Thus, inducing adult-like Th1 responses may be achieved in vivo by inducing (CD40L) or substituting for (IL-12 supplementation) optimal activation of neonatal APC. However, these immunomodulatory effects appear limited to certain antigen-presentation approaches and may not be broadly applicable to vaccines.
authors.affiliation: World Health Organization Collaborating Centre for Neonatal Vaccinology, University of Geneva Medical School, Geneva, Switzerland. jiri.kovarik@medecine.unige.ch
authors.forename: J
authors.initials: J
authors.lastname: Kovarik
authors.forename: X
authors.initials: X
authors.lastname: Martinez
authors.forename: M
authors.initials: M
authors.lastname: Pihlgren
authors.forename: P
authors.initials: P
authors.lastname: Bozzotti
authors.forename: M H
authors.initials: MH
authors.lastname: Tao
authors.forename: T J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: T F
authors.initials: TF
authors.lastname: Wild
authors.forename: P H
authors.initials: PH
authors.lastname: Lambert
authors.forename: C A
authors.initials: CA
authors.lastname: Siegrist
mesh_terms: D000276:Adjuvants, Immunologic; D000375:Aging / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand; D006389:Hemagglutinins, Viral / Q000276:immunology; D007114:Immunization; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D008222:Lymphokines / Q000032:analysis; D008458:Measles Vaccine / Q000276:immunology*; D008459:Measles virus / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D000914:Antibodies, Viral; D000942:Antigens, Bacterial; D019013:CD40 Antigens; D006389:Hemagglutinins, Viral; D008222:Lymphokines; D008458:Measles Vaccine; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D013745:Tetanus Toxoid; D023201:CD40 Ligand; D018664:Interleukin-12