Characterization of the concentration and binding affinity of WT-induced antibodies against the Omicron BA.1 subvariant

The coronavirus disease 2019 (COVID-19) pandemic, caused by the rapid spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed more than 6.9 million lives worldwide.

Several variants of SARS-CoV-2 have arisen due to genomic mutations of the ancestral or wild-type (WT) SARS-CoV-2 strain. Of these variants, those classified as variants of concern (COVs) pose a greater challenge to long-term vaccine- and/or infection-induced immunity.

Many COVID-19 vaccines have been developed targeting the spike protein of the SARS-CoV-2 WT strain. It is therefore important to assess the effectiveness of these vaccines against new strains of SARS-CoV-2, in particular VOCs.

Background

More recently, the SARS-CoV-2 Omicron variant has circulated in the majority of countries around the world. Since the emergence of COVs, the Omicron variant has proven to be the most antigenically distinct strain.

Most mutations in this strain affect the S1 subdomain of the spike protein, which facilitates varying degrees of immune evasion and a significant decrease in long-term protection against reinfection.

Although numerous studies have indicated the decrease in neutralizing capacity of antibodies induced by earlier variants or vaccination, few documents regarding the avidity of persistent antibodies are available. Antibody avidity describes the strength of binding to the target antigen, which is extremely important for antibody functionality.

Previous studies have shown that avidity increases with time after contact through the maturation of B cells in germinal centers. This implies the possibility of compensating for the decreasing effect of antibodies up to a certain level.

A recent Frontiers in immunology The study characterized the concentration and binding affinity of antibodies induced by the SARS-CoV-2 WT strain against the Omicron BA.1 (OM) subvariant.

About the study

A post-infection cohort comprising seropositive adult participants of the Ischgl-2 seroprevalence study was developed. This cohort included participants who became infected with SARS-CoV-2 during the first wave of infection in March/April 2020. Blood samples from the participants were collected in November 2020, i.e. 7-8 months after contact with the pathogen. None of the participants reported a second infection during blood collection (sampling).

This cohort also included participants in the ShieldVacc-2 study, who received their second dose of the COVID-19 vaccine (BioNTech/Pfitzer) in March/April 2021. For these participants, blood samples were collected in November 2021, i.e. 7-8 months after contact with the antigen.

A total of 690 age- and sex-matched participants were recruited, of whom 354 received a double mRNA vaccine and 336 were infected with WT. Both groups had a higher number of male participants.

Study results

Consistent with previous studies, the current study found that antibodies generated by WT infection have lower binding and neutralization antibody titer to OM epitopes. Even though the reduced antibody concentration against the mutated antigen was expected, an unwarranted antibody avidity for the Omicron variant was found not only to be non-inferior to the WT avidity. Interestingly, the binding affinity was found to be slightly higher towards the OM antigen in all participants of the cohort.

Notably, this study indicated that non-neutralizing antibodies and antibody avidity have a protective role against serious infections. This factor could have prevented the severity of the Omicron era. In the future, researchers need to determine if a structural change in epitopes associated with a mutation led to the aforementioned observation.

Analysis of blood samples indicated a significant decline in IgG antibodies after an initial peak within the first three months after antigen contact. This observation was especially true for vaccinated participants. After the initial surge, antibody titers declined and reached a stable level, and this concentration persisted for at least a year.

Previous studies have indicated the possibility of structural changes after mutations, which could affect antibody functionality and binding capacity. However, the current study indicated a reduced but significant preservation of binding capacity against the mutated variant in both the convalescent and vaccinated groups. Compared to the WT-infected group, the vaccinated group showed higher antibody titers against OM.

The concentration-matching avidity assay adopted in this study provided better comparability of binding affinity due to the fact that avidity maturation is a time-dependent process.

Strengths and limitations

One of the strengths of this study is its large sample size and the comparability of the sex and age distribution between the two groups, i.e. WT-infected and vaccinated. In addition, this study used ELISA tests validated according to European standards.

Although prior infection in the vaccinated cohort was ruled out based on participants’ infection history, there is a possibility of residual risk from past infections that could impact the results. The use of the Omicron subvariant (BA.1) limited the generalizability of the study.

The current study focused on humoral aspects of immunity and did not consider cellular immunity due to lack of relevant data. Future research needs to analyze the synergistic effect of the two types of immunities on SARS-CoV-2 disease outcome.

Despite the limitations, this study revealed the presence of a non-negligible proportion of binding antibodies in the study cohort effective against the Omicron BA.1 variant.