The serological response to SARS corona virus-2 is characterized by frequent incomplete maturation of functional affinity (avidity)

Abstract

The humoral immune systems controls viral infections through recognition of critical viral target structures, selective proliferation stimulation of IgM-presenting B cells, class switch to IgG-generating B cells and subsequent affinity maturation of IgG. Affinity maturation is achieved through proliferation, hypermutation and clonal selection of IgG-generating B cells (1-4). The establishment of high affinity IgG is essential for sustained protective antiviral effects (5-10). While analyzing the maturation of functional affinity (avidity) of IgG towards SARS CoV-2 nucleoprotein, surface protein and its receptor-binding domain, we realized that avidity maturation was frequently not completed after infection. This finding gives insight into the biological strategy of SARS CoV-2 and is important for serodiagnosis. Incomplete avidity maturation might explain the observed decline of the humoral response (11-14), allow for secondary SARS CoV-2 infections and prevent the establishment of herd immunity. Therefore, future immunization strategies should achieve the goal to induce neutralizing IgG of high avidity.

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

“…The repeated findings on low avidity of IgG directed towards SARS‐CoV‐2 antigens, even several months after onset of clinical symptoms 11,13,14,19–21 ; are unique in viral serodiagnostics so far. Though Luo et al 12 stated that there was a strong correlation between avidity or IgG towards RBD and days after onset of symptoms, their findings are also supporting the findings on low avidity of IgG towards SARS‐CoV‐2 antigens, as the authors had used the very low concentration of 3 M urea in their study.…”

“…The preceding figures have shown that the serological response towards SARS-CoV-2, as well as towards seasonal coronaviruses frequently may enface incomplete avidity maturation, in line with our previous findings. 11 The avidity determination in individual sera therefore does not always allow to immediately distinguish between (i) immature avidity and (ii) low avidity due to just ongoing acute infection. Careful quantitation of avidity in combination with testing a subsequent serum can, however, easily resolve such questions.…”

“…The use of this test system, led to the surprising result that avidity maturation of IgG towards SARS-CoV-2 antigens was frequently incomplete, and that incomplete avidity maturation seemed to be due to a discontinuous kinetics of avidity maturation rather than to a too short time of observation. 11 Therefore, even several months after infection, most of the sera from coronavirus disease 2019 (COVID-19) patients showed immature avidity of IgG towards SARS-CoV-2 antigens. Interestingly, the degree of avidity maturation was higher in patients with more severe disease.…”

The potential significance of high avidity immunoglobulin G (IgG) for protective immunity towards SARS-CoV-2

“…Bauer et al, 2021a , defined a mode of analysis that should allow to use avidity determination for the discrimination between acute and past SARS-CoV-2 infections despite low overall avidity. In a follow-up study with 93 sera from 70 SARS-CoV-2-infected Covid-19 outpatients, the frequent incomplete avidity maturation of IgG towards SARS-CoV-2 NP, RBD and S1 was confirmed ( Bauer et al, 2021b ). This study provided evidence that the low avidity found in most cases was due to discontinuous avidity maturation after an initial increase, rather than due to unusually slow avidity maturation.…”

“…The subsequent analysis of outpatients with COVID-19 and SARS-CoV-2 infection confirmed by positive PCR, led, however, to a rather unexpected result ( Bauer et al, 2021a , Bauer et al, 2021b ). In contrast to the regular interaction between the humoral immune system and viruses, the avidity of IgG towards SARS-CoV-2 antigens seemed to remain low in the majority of patients, even several months after the onset of clinical symptoms.…”