Antibody Avidity and Neutralizing Response against SARS-CoV-2 Omicron Variant after Infection or Vaccination

Abstract

Background. The recently emerged SARS-CoV-2 Omicron variant exhibits several mutations on the spike protein, enabling it to escape the immunity elicited by natural infection or vaccines. Avidity is the strength of binding between an antibody and its specific epitope. The SARS-CoV-2 spike protein binds to its cellular receptor with high affinity and is the primary target of neutralizing antibodies. Therefore, protective antibodies should show high avidity. This study aimed at investigating the avidity of receptor-binding domain (RBD) binding antibodies and their neutralizing activity against the Omicron variant in SARS-CoV-2 infected patients and vaccinees. Methods. Samples were collected from 42 SARS-CoV-2 infected patients during the first pandemic wave, 50 subjects who received 2 doses of mRNA vaccine before the Omicron wave, 44 subjects who received 3 doses of mRNA vaccine, and 35 subjects who received heterologous vaccination (2 doses of adenovirus-based vaccine plus mRNA vaccine) during the Omicron wave. Samples were tested for the avidity of RBD-binding IgG and neutralizing antibodies against the wild-type SARS-CoV-2 virus and the Omicron variant. Results. In patients, RBD-binding IgG titers against the wild-type virus increased with time, but remained low. High neutralizing titers against the wild-type virus were not matched by high avidity or neutralizing activity against the Omicron variant. Vaccinees showed higher avidity than patients. Two vaccine doses elicited the production of neutralizing antibodies, but low avidity for the wild-type virus; antibody levels against the Omicron variant were even lower. Conversely, 3 doses of vaccine elicited high avidity and high neutralizing antibodies against both the wild-type virus and the Omicron variant. Conclusions. Repeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD.

The neutralizing response to SARS-CoV-2 Omicron variants BA.1 and BA.2 in COVID-19 patients and homologous and heterologous vaccinees

“…Conversely, inadequate levels of avidity maturation can heighten susceptibility to viral infection. 13 …”

Differential avidity determination of IgG directed towards the receptor‐binding domain (RBD) of SARS‐CoV‐2 wild‐type and its variants in one assay: Rational tool for the assessment of protective immunity

“…In addition, the epitopes on omicron RBD that are shared with WT RBD, seem to bind specific IgG with lower avidity than the WT RBD 10,33 . In line with these findings, cross‐protection between IgG induced by a WT‐specific vaccine and the omicron variant requires at least three vaccination steps, whereas the reaction with the homologous proteins can reach high avidity already after two vaccination steps 29,35–37 …”

“…Though the recent dominant variant omicron carries more than 30 mutations in its spike protein, most of them in RBD, its amazing efficiency of transmission does not seem to depend on further enhancement of RBD/ACE2 affinity 10,33,34 . Rather, the efficiency of the omicron variant seems to be based on its immune escape phenotype 10,33–36 . This phenotype is impressively demonstrated (i) by lack of the majority of monoclonal antibodies that neutralize SARS‐CoV‐2 WT to neutralize the omicron variant, 10,34,36 and by the reduced binding of IgG from convalescent sera to the spike protein 33 .…”

“…10,33,34 Rather, the efficiency of the omicron variant seems to be based on its immune escape phenotype. 10,[33][34][35][36] This phenotype is impressively demonstrated (i) by lack of the majority of monoclonal antibodies that neutralize SARS-CoV-2 WT to neutralize the omicron variant, 10,34,36 and by the reduced binding of IgG from convalescent sera to the spike protein. 33 In conclusion, RBD of the omicron and the WT strain seem to share only a relatively low number of overlapping, protection-relevant epitopes.…”

“…10,33 In line with these findings, crossprotection between IgG induced by a WT-specific vaccine and the omicron variant requires at least three vaccination steps, whereas the reaction with the homologous proteins can reach high avidity already after two vaccination steps. 29,[35][36][37] The present epidemiological situation characterized by the complexity of the dynamics of variants, in combination with the focus of serological test systems and vaccines on the WT strain of SARS-CoV-2 demands the establishment of rapid and conclusive test systems. These should also allow determining the quality, that is the avidity of IgG directed towards RBD of the various variants.…”