Model-based inference of neutralizing antibody avidities against influenza virus

Abstract

To assess the response to vaccination, quantity (concentration) and quality (avidity) of neutralizing antibodies are the most important parameters. Specifically, an increase in avidity indicates germinal center formation, which is required for establishing long-term protection. For influenza, the classical hemagglutination inhibition (HI) assay, however, quantifies a combination of both, and to separately determine avidity requires high experimental effort. We developed from first principles a biophysical model of hemagglutination inhibition to infer IgG antibody avidities from measured HI titers and IgG concentrations. The model accurately describes the relationship between neutralizing antibody concentration/avidity and HI titer, and explains quantitative aspects of the HI assay, such as robustness to pipetting errors and detection limit. We applied our model to infer avidities against the pandemic 2009 H1N1 influenza virus in vaccinated patients (n = 45) after hematopoietic stem cell transplantation (HSCT) and validated our results with independent avidity measurements using an enzyme-linked immunosorbent assay with urea elution. Avidities inferred by the model correlated with experimentally determined avidities (ρ = 0.54, 95% CI = [0.31, 0.70], P < 10−4). The model predicted that increases in IgG concentration mainly contribute to the observed HI titer increases in HSCT patients and that immunosuppressive treatment is associated with lower baseline avidities. Since our approach requires only easy-to-establish measurements as input, we anticipate that it will help to disentangle causes for poor vaccination outcomes also in larger patient populations. This study demonstrates that biophysical modelling can provide quantitative insights into agglutination assays and complement experimental measurements to refine antibody response analyses.

HLA antibody affinity determination: From HLA‐specific monoclonal antibodies to donor HLA specific antibodies (DSA) in patient serum

“…Thinking biologically, a humoral immune response with low affinity antibodies can be balanced with a respective high antibody concentration (and vice versa). Indeed, our results demonstrate an association between high affinity and low concentration, in line with observations on influenza virus specific antibodies 58 . The absolute serum DSA‐levels determined (Table 4 and Figure 7), although presumed to be slightly biased by the unique isotype/subclass composition of individual DSA (Table 4 ), are comparable with the sparse published HLA antibody concentrations to date ( n = 5; 6.1 nM, 15.3 nM, 38.7 nM, 60 nM, 68 nM) 29,59 and reasonably comparable to those published for influenza‐specific IgG post‐vaccination 57 and for SARS‐2‐CoV‐2‐specific IgGs 60 …”

“…Indeed, our results demonstrate an association between high affinity and low concentration, in line with observations on influenza virus specific antibodies. 58 The absolute serum DSA-levels determined (Table 4 and Figure 7), although presumed to be slightly biased by the unique isotype/subclass composition of individual DSA (Table 4), are comparable with the sparse published HLA antibody concentrations to date (n = 5; 6.1 nM, 15.3 nM, 38.7 nM, 60 nM, 68 nM) 29,59 and reasonably comparable to those published for influenza-specific IgG post-vaccination 57 and for SARS-2-CoV-2-specific IgGs. 60 Can the Luminex platform, available in most HLA laboratories worldwide also serve to determine DSAaffinity?…”

A nanoparticle vaccine displaying the ookinete PSOP25 antigen elicits transmission-blocking antibody response against Plasmodium berghei

“…Antibody avidity is an essential parameter of the quality of vaccine-induced immune responses [ 31 , 32 ]. The avidity of the serum IgG collected on days 28 and 38 was assessed by employing a chaotropic agent (urea) to disrupt the interactions between the antibody and the coating antigen in a modified ELISA assay [ 33 ].…”

Multi-strain modeling of influenza vaccine effectiveness in older adults and its dependence on antigenic distance

“…HI titer refers to the highest serum dilution that fully inhibits hemagglutination due to antibody binding [76]. We used the theoretical model of Linnik et al (2022) [76] to predict the log2 HI titers from values of the concentration of specific neutralizing antibodies in serum () and their avidity for HA () by fitting their phase diagram [76] : where represents the relative proportion of HA antigens with respect to NA antigens in natural infection or in vaccination [60–70] (0.9). This equation returns continuous non-integer values of log2 HI titers to be compared to integer values returned by real HI assays.…”

“…HI titer refers to the highest serum dilution that fully inhibits hemagglutination due to antibody binding [76]. We used the theoretical model of Linnik et al (2022) [76] to predict the log2 HI titers from values of the concentration of specific neutralizing antibodies in serum (Blood.ig) and their avidity for HA (kAvidityHAspec) by fitting their phase diagram [76] : Initialization of a prior immunity with the historical strain An individual's previous antigen exposure through vaccination or infection may lead to a baseline level of immunity against influenza which may be highly heterogeneous across a population [77]. The initialized baseline level is assumed to be specific to a generic historical (H) strain that represents remaining immunity against both H1N1 and H3N2 viral subtypes (possibly from several strains within these subtypes .…”