The challenge of avidity determination in SARS‐CoV‐2 serology

Abstract

The serological responses towards severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein, receptor-binding domain (RBD), and spike protein S1 are characterized by incomplete avidity maturation. Analysis with varying concentrations of urea allows to determine distinct differences in avidity maturation, though the total process remains at an unusually low level. Despite incomplete avidity maturation, this approach allows to define early and late stages of infection. It therefore can compensate for the recently described irregular kinetic patterns of immunoglobulin M and immunoglobulin G (IgG) directed towards SARS-CoV-2 antigens. The serological responses towards seasonal coronaviruses neither have a negative nor positive impact on SARS-CoV-2 serology in general. Avidity determination in combination with measurement of antibody titers and complexity of the immune response allows to clearly differentiate between IgG responses towards seasonal coronaviruses and SARS-CoV-2.Cross-reactions seem to occur with very low probability. They can be recognized by their pattern of response and through differential treatment with urea. As high avidity has been shown to be essential in several virus systems for the protective effect of neutralizing antibodies, it should be clarified whether high avidity of IgG directed towards RBD indicates protective immunity. If this is the case, monitoring of avidity should be part of the optimization of vaccination programs.

BNT162b2 mRNA SARS-CoV-2 Vaccine Elicits High Avidity and Neutralizing Antibodies in Healthcare Workers

“…So far, a number of studies evaluated the anti-Spike or anti-receptor binding domain (RBD) antibody titer [ 5 , 6 , 7 ] and their neutralizing activity [ 8 ], but little is known about the avidity of antibodies elicited by the mRNA SARS-CoV-2 vaccine [ 9 ]. Moreover, the extent of affinity maturation in COVID-19 patients and its impact on the clinical course of the disease is still a subject of active investigation [ 10 , 11 , 12 ].…”

SARS coronavirus outbreaks past and present—a comparative analysis of SARS-CoV-2 and its predecessors

“…In which, the binding strength between IgG and its epitope, and strength of the multivalent interactions where both antigen interacting with multiple IgG antigen-binding sites greatly reduced [ 66 ]. Besides that, the avidity maturation of the IgG antibody allows the differentiation of acute and past SARS-CoV-2 infection, albeit not completely certain [ 73 ]. Bauer and colleagues stated that low avidity of IgG antibody illustrate an acute sars-cov-2 infection, intermediate avidity IgG might indicate recent infection and high avidity IgG might indicate a past infection [ 74 ].…”

Comment to the manuscript by William P. Hausdorff and Jorge Flores: Low-dose and oral exposure to SARS-CoV-2 may help us understand and prevent severe COVID-19, IJID 103 (2021) 37–41

“…They therefore concluded that only IgG with high affinity for the S protein can efficiently interfere with infection. 2) Recent findings show frequent incomplete avidity maturation of IgG towards SARS-CoV-2 nucleoprotein (NP), surface protein-1 (S1) and receptor-binding domain (RBD) (Strömer et al, 2020;Liu et al, 2020;Bauer et al, 2020Bauer et al, , 2021. Avidity (i. e. the strength of binding between IgG and epitope) matures in parallel to affinity.…”

“…More than 70 percent of Covid-19 outpatients do not generate high avidity IgG at five months after the onset of disease (Bauer et al, 2020(Bauer et al, , 2021. Kinetic analysis revealed that avidity maturation stopped in parallel to the break in IgG production (Bauer et al, 2020(Bauer et al, , 2021 which seems to be leading to waning antibody levels (Seow et al, 2020). Therefore, in the majority of cases, IgG directed towards SARS-CoV-2 RBD can be predicted not to be efficient with respect to interference with the high affinity interaction between ACE2 and RBD.…”

“…3) In many viral systems, the failure to achieve complete avidity maturation leads to a failure in protection towards infection and disease (reviewed in Bauer, 2021). 4) The immature avidity of the IgG response towards seasonal coronaviruses (Bauer et al, 2020(Bauer et al, , 2021) might be the biological basis for the observed repeated cycles of reinfections by these viruses (Edridge et al, 2020;Galanti and Shaman, 2020).…”