Neutralizing antibody levels to different SARS-CoV-2 epitopes fluctuate over time

By Colin Lightfoot, M.Sc. Infection and ImmunityFeb 15 2022Reviewed by Benedette Cuffari, M.Sc.

The potential utility of neutralizing antibodies as anti-viral treatments have led many researchers to study the humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Potent neutralizing antibodies primarily target epitopes on the spike (S) glycoprotein of SARS-CoV-2's, which consists of S1 and S2 subunit monomers.

The receptor-binding domain (RBD) of the S1 subunit interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor to mediate entry of the virus into host cells. The RBD is considered the most important target for effective neutralization. Notably, the S1 subunit also contains the N-terminal domain (NTD), which interacts with sialic acids or coreceptors.

Study: Dynamics of Neutralizing Antibodies and Binding Antibodies to Domains of SARS-CoV-2 Spike Protein in COVID-19 Survivors. Image Credit: Kateryna Kon / Shutterstock.com

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Background

The length of protective immunity against SARS-CoV-2 has a significant impact on the incidence of reinfections and vaccination breakthrough infections, as well as the overall trajectory of the coronavirus disease 2019 (COVID-19) pandemic.

Recently, researchers have discovered that neutralizing antibody levels quickly subside in the first two to three months following infection and continue to gradually decline after this point. While nucleocapsid (NP) and S-specific immunoglobulin G (IgG) titers decrease, significant neutralizing activity has been reported to remain for up to 12 months in approximately 20% of patients after natural infection.

In a recent study posted to the Research Square* server, which is under consideration for publication in the journal Archives of Virology, researchers examine the longitudinal trend of binding antibodies to the domains of SARS-CoV-2 that are believed to be responsible for neutralizing activities in COVID-19 patients who have recovered from the disease.

Study findings

A total of 307 convalescent sera samples obtained sequentially from 35 patients from two to 12 months after recovery were used to assess their micro-neutralization of SARS-CoV-2. Enzyme-linked immunosorbent assay (ELISA) was also used to analyze the binding antibodies present in these samples.

Blood samples from the participants were taken every two to three weeks and analyzed for neutralizing antibody titers, with the blood collection schedule ending when the neutralizing antibody titer fell below 160.  Some donor sera samples followed a similar pattern in neutralizing titers and RBD, NTD, S2, and NP binding levels, which all reduced over the course of the investigation.

Within three months of when the first blood sample was obtained, neutralizing antibody titers in nine donors had dropped below 160. After 13, 33, and 23 weeks, the neutralizing antibody titers of three more donors were all below 160.

Ten donors exhibited high neutralizing antibody titers at the start of the study; however, these levels were quickly lost after two months, thereby leaving 13 donors with antibody titer data spanning three to twelve months. Over the course of three months, these 13 donors had consistently high neutralizing titers.

One year after the first collection, donor IDs CCP63000073 and CCP63000189 still exhibited strong neutralizing titers of 640 and 1280, respectively. Because the SARS-CoV-2 RBD is a common target of SARS-CoV-2-neutralizing antibodies, a comparable relationship between neutralizing titers and RBD binding levels was observed in ten donors ID.

Eight donors also exhibited persistently high neutralizing titers; however, their RBD binding levels gradually declined. In these participants, the reduction in RBD binding antibody levels was faster than the decline in antibodies to the other domains. Eventually, the number of binding antibodies to RBD decreased rapidly, whereas neutralizing titers remained stable, thus indicating that other epitopes were important as well.

In most of the donor samples, binding antibodies specific to S2 remained steady or gradually declined. Donor ID CCP63000055, CCP63000077, and CCP63000189 all displayed a level of binding antibodies to S2 for 35, 43, and 47 weeks, respectively, that were relatively high and consistent.

These serum samples were also examined for neutralizing titers against a SARS-CoV-2 Delta variant. To this end, the scientists discovered that sera with high neutralizing titers and high S2-binding antibodies did not demonstrate significantly higher cross-neutralization to the Delta variant when compared to sera with lower S2-binding antibodies.

Despite the poor antibody binding to the NTD and RBD domains, the persistent neutralizing activity appeared to be primarily directed at changeable S1 epitopes.

Implications

Antibodies to SARS-CoV-2 recognize various viral epitopes, all of which may diminish at different rates throughout time; thus, their role in neutralizing activity may also fluctuate. Anti-RBD antibodies may not be long-lasting, despite the fact that RBD is such a dominant epitope that it can rapidly elicit robust neutralizing antibodies.

The mechanism responsible for the varied longevity of distinct antibodies is unknown. Therefore, more research into the longevity of specific antibodies is needed to improve vaccine design and ultimately produce long-lasting protection against COVID-19.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources