Activation of monocytes by three OspA vaccine candidates: lipoprotein OspA is a potent stimulator of monokines.
The outer surface protein (Osp) A of Borrelia burgdorferi is the first Lyme antigen to be tested in a vaccine for humans. Three forms of OspA vaccine candidates were investigated by the induction of the cytokines interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha, IL-10 and interferon (IFN)-gamma as markers of monocyte activation and immune stimulation: lipidated OspA (L-OspA), non-lipidated OspA (NL-OspA), and a fusion protein of 81 amino acids of the nonstructural protein 1 of influenza virus with OspA (NS1-OspA). All OspA preparations induced IL-1 beta, IL-6 and TNF-alpha in a concentration-dependent manner with peak levels at 12-24 h. These cytokines were entirely derived from the monocyte fraction. In peripheral blood mononuclear cells from 10 healthy donors, L-OspA at 10 micrograms ml-1 induced up to 4-fold more IL-1 beta, IL-6, and TNF-alpha than the other OspA preparations (P < or = 0.0068), followed by NS1-OspA, which was still superior to NL-OspA. L-OspA. L-OspA also induced high levels of IL-10 within 24 h but no significant amounts of IFN-gamma. This superior stimulating activity of L-OspA on unstimulated monocytes predominantly depended on N-terminal lipidation of OspA. Similarities to other lipoproteins and synthetic lipopeptides suggest that lipidation confers adjuvant properties on OspA. High induction of IL-10 by L-OspA further suggested a negative feedback on monocyte activation by the lipidated form. The in vitro results are in line with in vivo results in mice, monkeys and humans and indicates that lipoprotein OspA has the best potential for induction of a protective effect in humans, compared to non-lipidated antigens.
Häupl
T
T
Department of Medicine III, Charité, Humboldt University, Berlin, Germany. thomas.haeupl@rz.hu-berlin.de
Landgraf
S
S
Netusil
P
P
Biller
N
N
Capiau
C
C
Desmons
P
P
Hauser
P
P
Burmester
G R
GR
D000276:Adjuvants, Immunologic; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology*; D001428:Bacterial Vaccines; D015748:Borrelia burgdorferi Group / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008074:Lipoproteins; D008193:Lyme Disease / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D015846:Monokines / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D007375:Interleukin-1; D015850:Interleukin-6; D008074:Lipoproteins; D015846:Monokines; C072045:OspA protein; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; D016753:Interleukin-10; D007371:Interferon-gamma