Study attempts to standardize humoral immune Correlates of Protection (CoP) in COVID-19

The World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) pandemic in March 2020, owing to the rapid worldwide spread of its causative virus: severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This is a positive-sense RNA virus that causes mild to critical infection. Several COVID-19 vaccines have received emergency authorization by national regulatory authorities in different parts of the world and, subsequently, vaccination programs have been initiated in many countries.

Owing to the lack of Correlate of Protection (CoP) to COVID-19, the efficacy of these vaccines has been evaluated based on placebo-controlled clinical trials, which involved a large number of candidates who were naturally exposed to SARS-CoV-2. Although this approach turned out to be successful, it proved to be logistically demanding and very expensive. Scientists have reported that the SARS-CoV-2 variants are more infectious and have the potential to evade the immune response of the host. Hence, for the regulatory bodies and vaccine manufacturing companies, determining the efficiency of the approved vaccines against SARS-CoV-2 variants has become essential.

Previous studies have reported that the magnitude of the antibody response depends on the severity of the COVID-19 disease. For instance, scientists have revealed that patients who recovered from severe infection have high virus-neutralizing antibodies (nAb) titers. The cellular immune response plays an important role in the clearance of internal viral antigens. The anti-viral immunity of non-neutralizing antibodies is found to be directed towards the Nucleocapsid (N) antigen of SARS-CoV-2. In this regard, one mechanism involves the cytosolic antibody receptor TRIM21, which seizes the antibody-antigen complexes and hastens the degradation process. It also enables the loading of antigenic peptides in nascent MHC molecules and, thereby, readily presents antigens to the T cells. The Humoral Immune Correlates for COVID-19 Project (HICC) focuses on determining the humoral immune response to SARS-CoV-2 and establishes the mechanism behind the immunity that protects an individual against COVID-19 disease.

A new study, released on the medRxiv* preprint server, aims to identify antibody-based biomarkers associated with the humoral immune response that could be a standard CoP candidate for COVID-19. Further, standardization of research methods to measure these biomarkers has also been conducted.

In this study, the researchers utilized data from vaccine trials and epidemiological studies that have determined virus-neutralizing antibodies (Nab) and SARS-CoV-2 antigen-specific binding antibodies as CoP candidates. The team also followed the WHO international standard as a benchmark criterion to evaluate the response of neutralizing antibodies, and also assessed a large number of binding antibody assays. The researchers compared the convalescent sera from the SARS-CoV-2 infected patients, seropositive healthcare workers (HCW), and seronegative HCW. The antibody levels of the samples were expressed in International Units (INU) for virus neutralization assays or International Binding Antibody Units (BAU) for ELISA tests.

For the detection of SARS-CoV-2-specific IgG and IgM antibodies, the present study has used commercial and non-commercial antibody binding assays and a lateral flow test. The S, N, and RBD proteins have been determined using a high throughput multiplexed particle flow cytometry assay. IgM, IgA, and IgG have been measured using a multiplex antigen semi-automated immuno-blotting assay. The team also used the pseudotyped microneutralization test (pMN) and electroporation-dependent neutralization assay (EDNA).

Previous studies reported a positive correlation between spike-specific antibodies and nAb. These results have been confirmed by the current study, which has also revealed that Nab of COVID-19 convalescent sera is strongly connected with spike-specific IgG and IgA binding antibodies. Hence, the researchers believe that nAb can be used as a biomarker of COVID-19 immunity. The EDNA assay revealed a significant reduction of virus replication which correlates with the N-specific antibody levels of the sera.

The present study has provided experimental evidence to show intracellular virus neutralization is greater in COVID-19 patients than in seropositive samples. The current research suggests that in terms of antigen specificity, IgA responses are similar to IgG. The mucosal IgA might be an important component for neutralizing the SARS-CoV-2. The researchers of the present study have also reported the presence of IgM in many individuals among the COVID-19 patients and seropositive HCW cohorts.

The main findings of the current study are listed below:

a) A positive correlation between clinical severity and SARS-CoV-2-specific antibodies was determined from the data of epidemiological studies and vaccine clinical trials.

b) In convalescent samples, a strong association between nAb and S-and RBD-specific antibody levels was observed, which was measured by the pMN assay.

c) The intracellular neutralization correlated very well with N-specific antibody levels.

d) Different antigen-specific reactivity patterns of IgG, IgA, and IgM in seropositive samples were found.

The team’s study identified a range of assays and biomarkers of COVID-19 immunity that can be utilized to define CoP. The team believes that further analyses of this cohort would help determine the evolution of antigen-specific antibody responses over time.

*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.

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