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

Abstract

Avidity is defined as the binding strength of immunoglobulin G (IgG) toward its target epitope. Avidity is directly related to affinity, as both processes are determined by the best fit of IgG to epitopes. We confirm and extend data on incomplete avidity maturation of IgG toward severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleoprotein (NP), spike protein‐1 (S1), and its receptor‐binding domain (RBD) in coronavirus disease 2019 (COVID‐19) patients. In SARS‐CoV‐2‐infected individuals, an initial rise in avidity maturation was ending abruptly, leading to IgG of persistently low or intermediate avidity. Incomplete avidity maturation might facilitate secondary SARS‐CoV‐2 infections and thus prevent the establishment of herd immunity. Incomplete avidity maturation after infection with SARS‐CoV‐2 (with only 11.8% of cases showing finally IgG of high avidity, that is, an avidity index > 0.6) was contrasted by regular and rapid establishment of high avidity in SARS‐CoV‐2 naïve individuals after two vaccination steps with the BioNTech messenger RNA (mRNA) Vaccine (78% of cases with high avidity). One vaccination step was not sufficient for induction of complete avidity maturation in vaccinated SARS‐CoV‐2 naïve individuals, as it induced high avidity only in 2.9% of cases within 3 weeks. However, one vaccination step was sufficient to induce high avidity in individuals with previous SARS‐CoV‐2 infection.

The anti-SARS-CoV-2 immunoglobulin G levels and neutralising capacities against alpha and delta virus variants of concern achieved after initial immunisation with vector vaccine followed by mRNA vaccine boost are comparable to those after double immunisation with mRNA vaccines

“…After the first vaccination nearly all vaccinees exhibited only low to intermediate avid anti-SARS-CoV-2 IgG, while after the second vaccine dose IgG of high avidity appeared in all cases. These results confirm and expand the existing knowledge on the development of highly avid anti-SARS-CoV-2 IgG after a second vaccination with an mRNA vaccine [28]. In line with this, VNA > 1:10 against the previously prevalent SARS-CoV-2 VOC B.1.1.7 (alpha) were observed after second immunisation which confirms our recent study [22].…”

Long-term decay of anti-RBD IgG titers after BNT162b2 vaccination is not mirrored by loss of neutralizing bioactivity against SARS-CoV-2

“…In COVID-19 patients, affinity maturation is potentially impaired by the dysfunction of germinal centres associated with severe disease [40] , [41] . Actually, longitudinal studies on functional affinity maturation after natural infection have produced heterogeneous results [21] , [30] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] with gender, age and COVID-19 severity likely playing a role in driving divergent pathways [42] , [43] , [48] . On the contrary, in vaccine recipients, affinity maturation seems to be guaranteed by the uploading and persistence of viral Spike antigen on dendritic cells of germinal centers up to 12 weeks after liposomal mRNA inoculation [54] , which in turn provide a solid background for long-term antigen presentation in germinal centres [55] and eventual achievement of high avidity values [30] , [35] , [36] , [56] .…”

“…Actually, longitudinal studies on functional affinity maturation after natural infection have produced heterogeneous results [21] , [30] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] with gender, age and COVID-19 severity likely playing a role in driving divergent pathways [42] , [43] , [48] . On the contrary, in vaccine recipients, affinity maturation seems to be guaranteed by the uploading and persistence of viral Spike antigen on dendritic cells of germinal centers up to 12 weeks after liposomal mRNA inoculation [54] , which in turn provide a solid background for long-term antigen presentation in germinal centres [55] and eventual achievement of high avidity values [30] , [35] , [36] , [56] . Notably, a study from Struck et al [30] , which directly assessed avidity of anti-SARS-CoV-2 sera from vaccinated subject using the chaotropic agent urea, have provided strong evidence that avidity significantly increases in the first two months after vaccination, which may also explains the persistence of high neutralizing bioactivity in the face of declining anti-RBD IgG over a longer period of time, as this study showed.…”

“…In fact, waning of binding Abs either after natural infection or vaccination might be countered by the maintenance of neutralizing capacity by ongoing affinity maturation of Spike-specific B lymphocytes [27] . Failure of affinity maturation has been previously associated with vaccine failure [28] and some Authors have advocated that the development of high affinity antibodies targeting multiple epitopes of RBD are needed for effective long-term protection against SARS-CoV-2 [29] , [30] , [31] , [32] . Available studies [30] , [33] , [34] have shown parallel increases in avidity values, neutralizing activity and quantitative anti-RBD antibody titres up to 8 weeks from the second dose of vaccine but these short-term analyses were not designed to prove whether quantitative RBD-antibody level would predict neutralizing bioactivity and clinical protection on the long-term, when divergent kinetics of immunogenicity markers may unmask functional mechanistic associations [16] , [22] .…”

Incomplete IgG avidity maturation after seasonal coronavirus infections

“…[9][10][11][12][13][14] Although there was an initial but limited increase in the avidity of IgG directed toward SARS-CoV-2 nucleoprotein (NP), spike protein-1 (S1) and the receptor-binding domain of the spike protein (RBD) after SARS-CoV-2 infection, avidity persisted at an untypical low or intermediate level, even up to 1 year after primary infection. 15 This novel picture of incomplete avidity maturation raised problems for the differentiation between the stages of infection. Even more importantly, these findings seemed to indicate that infections with SARS-CoV-2 might not necessarily lead to protective immunity.…”