Incomplete IgG avidity maturation after seasonal coronavirus infections

Abstract

In classical viral infections, the avidity of immunoglobulin G (IgG) is low during acute infection and high a few months later. As recently reported, SARS‐CoV‐2 infections are not following this scheme, but they are rather characterized by incomplete avidity maturation. This study was performed to clarify whether infection with seasonal coronaviruses also leads to incomplete avidity maturation. The avidity of IgG toward the nucleoprotein (NP) of the seasonal coronaviruses 229E, NL63, OC43, HKU1 and of SARS‐CoV‐2 was determined in the sera from 88 healthy, SARS‐CoV‐2‐negative subjects and in the sera from 70 COVID‐19 outpatients, using the recomLine SARS‐CoV‐2 assay with recombinant antigens. In the sera from SARS‐CoV‐2‐negative subjects, incomplete avidity maturation (persistent low and intermediate avidity indices) was the lowest for infections with the alpha‐coronaviruses 229E (33.3%) and NL63 (61.3%), and the highest for the beta‐coronaviruses OC43 (77.5%) and HKU1 (71.4%). In the sera from COVID‐19 patients, the degree of incomplete avidity maturation of IgG toward NP of 223E, OC43, and HKU1 was not significantly different from that found in SARS‐CoV‐2‐negative subjects, but a significant increase in avidity was observed for IgG toward NP of NL63. Though there was no cross‐reaction between SARS‐CoV‐2 and seasonal coronaviruses, higher concentrations of IgG directed toward seasonal coronaviruses seemed to indirectly increase avidity maturation of IgG directed toward SARS‐CoV‐2. Our data show that incomplete IgG avidity maturation represents a characteristic consequence of coronavirus infections. This raises problems for the serological differentiation between acute and past infections and may be important for the biology of coronaviruses.

Avidity of IgG to SARS-CoV-2 RBD as a Prognostic Factor for the Severity of COVID-19 Reinfection

“…In contrast, patients in the group with a severe (hospitalized) COVID-19 course showed low avidity of IgG, not only in the primarily infected persons (median value of 25%), but also in the reinfected individuals (28.4%) (groups of primarily and secondarily infected patients did not differ significantly, p = 0.72, Table 1 , Figure 1 c). It can be assumed that these patients did not develop effective humoral immunity after their first immunization, and that B-lymphocyte maturation did not occur completely, as described for other coronaviruses [ 34 , 36 ]. Evidence for this is the persistent low avidity of antibodies (AI 28.4%), despite the fact that 217 days had passed between the first and second infections in “severe” patients, which is normally sufficient for the maturation of antibodies (it takes 3 to 4 months to reach maturation, as is evident from the data on outpatients—see Figure 1 a above—and as known from other studies [ 18 , 19 , 20 ]).…”

“…As noted above, the production of high-avidity IgG is associated with the following events: A history of successful immunization, in a period of time that allows the immune system to finish the maturation of antibody-producing B-lymphocytes (3–4 months) [ 18 , 19 , 20 ]; The successful completion of B-lymphocyte maturation (as complete as it can be for beta-coronaviruses at all [ 34 , 36 ]), development of a stable immune response, and formation of a population of memory B-cells [ 10 ] which can produce IgG of already high avidity upon new infection; The improvement of the neutralizing (protective) ability of IgG—because only high-affinity and, therefore, high-avidity antibodies are relevant for virus neutralization, since they can effectively compete with ACE2 for binding to the RBD [ 27 , 28 , 32 , 34 ]. …”

“…The successful completion of B-lymphocyte maturation (as complete as it can be for beta-coronaviruses at all [ 34 , 36 ]), development of a stable immune response, and formation of a population of memory B-cells [ 10 ] which can produce IgG of already high avidity upon new infection;…”

“…It is known that in some immunized patients, IgG do not acquire high avidity [ 34 , 36 ] even after the time that is needed for B-lymphocyte maturation (3–4 months) [ 18 , 19 , 20 ]. It can be assumed that the adaptive immune system of these individuals has failed to mature B-lymphocytes; the proportion of high-affinity (and, therefore, virus-neutralizing) IgG in their serum is low, and they are at risk of reinfection and/or its negative outcome.…”

Vaccination versus infection with SARS‐CoV‐2: Establishment of a high avidity IgG response versus incomplete avidity maturation

“…Though a certain degree of avidity maturation in the low and intermediate range was seen with time for sera from patients with natural SARS-CoV-2 infection, only a minority of sera (11.8%) reached high avidity values (>0.6) (H−J) at 61−140 days after natural infection, whereas 78% of sera taken from vaccinated individuals had reached avidity indices above 0.6 between 6 and 25 days after the second vaccination (p < 0.001). The median values calculated from the data presented in Figure 6 As seasonal coronavirus infections are also frequently characterized by subsequent incomplete avidity maturation, 12,26 it may be speculated that maintaining low avidity of the IgG response, either through the suboptimal supply of the immune system with viral antigens or through impairment of avidity maturation, is part of the biology of coronaviruses in general. This might ensure the observed repeated waves of reinfection over time.…”