title: Threshold-free estimation of functional antibody titers of a group B streptococcus opsonophagocytic killing assay.
abstract: Opsonophagocytic killing assays (OPKA) are routinely used for the quantification of bactericidal antibodies in blood serum samples. Quantification of the OPKA readout, the titer, provides the basis for the statistical analysis of vaccine clinical trials having functional immune response endpoints. Traditional OPKA titers are defined as the maximum serum dilution yielding a predefined bacterial killing threshold value, and they are estimated by fitting a dose-response model to the dilution-killing curve. This paper illustrates a novel definition of titer, the threshold-free titer, which preserves biological interpretability while not depending on any killing threshold or on a postulated shape of the dose-response curve. These titers are shown to be more precise than the traditional threshold-based titers when using simulated and experimental group B streptococcus OPKA experimental data. Also, titer linearity is shown to be not measurable when using threshold-based titers, whereas it becomes measurable using threshold-free titers. The biological interpretability and operational characteristics demonstrated here indicate that threshold-free titers are an appropriate tool for the routine analysis of OPKA data.
authors.affiliation: Novartis Vaccines Research, via Fiorentina 1, Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Moraschini
authors.affiliation: Novartis Vaccines Research, via Fiorentina 1, Siena, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Passalacqua
authors.affiliation: Novartis Vaccines Research, via Fiorentina 1, Siena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Fabbrini
authors.affiliation: Novartis Vaccines Research, via Fiorentina 1, Siena, Italy.
authors.forename: Immaculada
authors.initials: I
authors.lastname: Margarit Y Ros
authors.affiliation: Novartis Vaccines Research, via Fiorentina 1, Siena, Italy.|Department of Statistics, University of Warwick, Coventry, UK.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rigat
mesh_terms: D000907:Antibodies, Bacterial / Q000097:blood*; D001428:Bacterial Vaccines / Q000627:therapeutic use; D001681:Biological Assay / Q000379:methods; D002986:Clinical Trials as Topic; D006801:Humans; D015233:Models, Statistical; D013223:Statistics as Topic; D013292:Streptococcus agalactiae / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines
keywords: data dimensionality reduction; four-parameter logistic regression; group B streptococcus; immune correlates of protection; opsonophagocytosis killing assay