The role of antibody concentration and avidity in antiviral protection

Science

Volumn 276, Issue 5321, 1997, Pages 2024-2027

  Bachmann, M F ^a,c   Kalinke, U ^a   Althage, A ^a   Freer, G ^a,d   Burkhart, C ^a,e   Roost, H P ^a   Aguet, M ^b   Hengartner, H ^a   Zinkernagel, R M ^a  

^a INSTITUTE OF EXPERIMENTAL IMMUNOLOGY   (Switzerland)

^b Swiss Cancer Institute   (Switzerland)

^c PRINCESS MARGARET HOSPITAL   (Canada)

^d UNIVERSITY OF PISA   (Italy)

^e UNIVERSITY OF BRISTOL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

NEUTRALIZING ANTIBODY;

ANTIBODY PRODUCTION; ANTIGEN BINDING; ANTIVIRAL ACTIVITY; ARTICLE; CONCENTRATION RESPONSE; IMMUNE RESPONSE; PRIORITY JOURNAL; VESICULAR STOMATITIS VIRUS; VIRUS INFECTION;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTIBODIES, VIRAL; ANTIBODY AFFINITY; ANTIBODY SPECIFICITY; BRAIN; ENZYME-LINKED IMMUNOSORBENT ASSAY; GLYCOPROTEINS; IMMUNIZATION, PASSIVE; IMMUNOGLOBULIN G; MEMBRANE GLYCOPROTEINS; MICE; MICE, INBRED BALB C; MICE, SCID; NEUTRALIZATION TESTS; RHABDOVIRIDAE INFECTIONS; VESICULAR STOMATITIS-INDIANA VIRUS; VIRAL ENVELOPE PROTEINS;

EID: 0030761775     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.276.5321.2024     Document Type: Article

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25. Avidity, neutralizing capacity, and neutralization rate constant as a measure for the on-rate were determined as described (6). In brief, avidity was determined from unmanipulated hybridoma supernatants with a solid-phase ELISA, in which intact virus particles were coated. Within a factor of 2, the measured avidities of the antibodies were largely independent of incubation temperatures at 22° and 37°C. The avidities of some antibodies were validated with an in-solution competition assay by determining the concentration of viral glycoprotein in solution required for half-maximal competition of antibody binding in the solid-phase ELISA (6). Neutralization rate constants were determined using the kinetics of virus neutralization as read-out. These values reflect physicochemical on-rates. Because VSV is polyvalent, the neutralization rate constant might give slightly higher values than the on-rate [J. Foote and H. Eisen, Proc. Natl. Acad. Sci. U.S.A. 92, 1254 (1995)].
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29. 4 PFU of VSV causes their death by day 2 to 3; protective concentrations of neutralizing antibodies extend survival to day 4 to 7. Because 1 PFU reaching nervous tissues will eventually be lethal, antibody concentrations about 5 to 10 times the protective concentration will usually prevent death after day 7.
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31. Neutralization requires covering of 30 to 50% of neutralizing sites (11). This is also illustrated by the observation that neutralization of VSV disappears within a 1:2 to 1:4 dilution step of the antibody, and in vivo protection vanishes in less than a 1:10 dilution step. This covering either blocks docking of VSV to receptors or inhibits fusion or pH-dependent conformational changes in the endosomes. All these mechanisms should operate similarly in vitro and in vivo. In this study, only the IgG2a-subclass antibodies analyzed confirm the conclusions drawn from all neutralizing IgG antibodies. Thus, the results seem not to be attributable to differences in specificity, nor to Fc and complement binding mechanisms, phagocytosis, or aggregations.
32. VSV-IND-specific neutralizing antibody titers were determined as described [M. F. Bachmann et al., J. Virol. 67, 3917 (1993)]. Viral titers in brains were determined as described (9). In brief, mice were exsanguinated under ether anesthesia and brains were removed aseptically. Brains were homogenized and viral titers were determined on Vero cells. To exclude the possibility that serum antibodies neutralized VSV particles in the brain after removal of the organ, we mixed VSV into the homogenized brain of a protected mouse and determined the viral titer. No reduction of VSV titer attributable to antibody in the brain was found. BALB/c (SCID) mice were obtained from the Institut für Zuchthygiene (Zürich, Switzerland) or from GSF GmbH (Oberschleissheim, Germany). Animal experiments were performed in accordance with Swiss federal law requiring use of minimal numbers of animals. VSV-IND (Mudd-Summers isolate) was originally obtained from D. Kolakofsky, University of Geneva.
33. We thank L. Lefrancois for mAb 25G9. Supported by Swiss National Science Foundation grant 31-32 195.91, the Kanton Zürich, and the Human Frontier Science Program.