In a recent study posted to the medRxiv* preprint server, researchers used serological measurements from a longitudinal cohort to evaluate the use of binding antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (RBD) as correlates of protection against the immune evasive Omicron subvariants BA.1 and BA.2.

Background

Although neutralizing antibodies have been considered to be a good indicator of protection against SARS-CoV-2 infections and severe coronavirus disease 2019 (COVID-19), neutralizing assays are labor and time-intensive. Depending on the immunoassays used and the time from infection or vaccination, binding antibody levels have been found to correlate with the neutralizing antibodies against SARS-CoV-2.

The validity of binding antibody levels as a correlate of protection has been explored by various individual and population-level studies, which have found that the risk of subsequent SARS-CoV-2 infections is lower when the binding antibody levels after vaccination or a previous infection are high.

However, many of these studies have been largely based on the ancestral SARS-CoV-2 strain, and the robustness of binding antibody levels as a correlate of protection against the immune-evading Omicron subvariants with mutations in the spike protein region remains unknown.

About the study

In the present study, the researchers used data from a population-based longitudinal cohort study in Geneva, Switzerland, where participants were invited to respond to an online questionnaire about the results of SARS-CoV-2 tests, vaccination status, and disease symptoms and severity and provide samples for a serological analysis at regular intervals during the study.

The researchers analyzed the serological data to understand the antibody trajectories and determine the correlates of protection during the dominance of the Omicron BA.1 and BA.2 subvariants. During the study period, the COVID-19 vaccines available in Geneva were the Pfizer/BioNTech and Moderna messenger ribonucleic acid (mRNA) vaccines and the Janssen adenoviral vector vaccine Ad26.COV2.S.

A quantitative immunoassay that measures the total antibodies, including immunoglobulins (Ig) G, A, and M, against the SARS-CoV-2 spike RBD was used to determine the binding antibody levels. Uncertainty in the serological measurements was determined by calculating the intra-lot and maximum coefficient of variation. The antibodies against the SARS-CoV-2 nucleocapsid protein were also measured to identify previous SARS-CoV-2 infections in vaccinated individuals since the mRNA and adenoviral vector vaccines only elicited anti-spike antibodies.

Information on polymerase chain reaction (PCR) and antigen test results were obtained from the Actionable Register of Geneva Outpatients and inpatients with SARS-CoV-2 (ARGOS) database. The antibody dynamics were statistically characterized by fitting the antibody trajectories from the longitudinal serological data to various kinetic models. These models also included data on booster doses and antibody decay based on age, sex, and vaccination history.

Furthermore, survival analysis methods were used to evaluate the use of binding antibody levels are correlates of protection during the exposure period of the Omicron subvariants BA.1 and BA.2 and calculate the risk of a positive SARS-CoV-2 test based on the level of binding antibodies, previous SARS-CoV-2 infections, and vaccination history.

Results

The results reported that high levels of anti-spike antibodies were correlated with a significant decrease in the risk of a positive SARS-CoV-2 test during the period of dominance of the Omicron BA.1 and BA.2 subvariants. Anti-spike antibody levels of 800 IU/ml or above were associated with a three-fold reduction in the risk of Omicron infections.

However, the same reduction in risk was not observed for participants who were vaccinated but did not have previous SARS-CoV-2 infections, which indicates that binding antibody levels can only be considered a correlate of protection against Omicron infections for vaccinated individuals with previous SARS-CoV-2 infections.

The results of the present study corroborated the findings of other similar studies that used in-house immunoassays. Furthermore, another study by the same researchers that evaluated the neutralization capacity among vaccinated infected and uninfected participants found that the level of anti-spike antibodies did not correlate with that of neutralization antibodies against the Omicron subvariants in vaccinated uninfected individuals but did in vaccinated individuals with previous SARS-CoV-2 infections.

Cumulatively, the results provided evidence that hybrid immunity from vaccinations and previous SARS-CoV-2 infections provide the best protection against the Omicron subvariants. However, the authors mentioned whether binding antibody levels can be used as a correlate of protection against infection from other Omicron subvariants with stronger immune-evading abilities remains unclear.

Emergent Omicron subvariants carrying novel mutations may impact the binding antibody levels, and the validity of anti-spike RBD antibodies as a correlate of protection would need to be re-examined.

Conclusions

Overall, the results suggested that binding antibody levels can serve as a correlate of protection against Omicron subvariants in individuals with hybrid immunity from vaccinations and previous SARS-CoV-2 infections.

With the emergence of Omicron subvariants and other SARS-CoV-2 variants containing novel mutations that allow them to escape humoral immunity, the validity of SARS-CoV-2 binding antibodies as a measurement of protection will have to be re-examined.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.