Researchers take steps to standardize correlates of protection against SARS-CoV-2

Researchers in the UK and Germany have identified a range of assays and biomarkers of humoral (antibody) immunity against coronavirus disease 2019 (COVID-19) that can be used to define correlates of protection in future studies.

Wherever suitable, antibody-based parameters were expressed in International Units (IU) and Binding Antibody Units (BAU).

“The adoption of common results reporting unitage in IU and BAU as those described in this study would eventually facilitate comparative analyses of data generated by immunogenicity studies performed by different teams in different parts of world,” says Jonathan Heeney from the University of Cambridge and colleagues.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.

Correlates of protection need to be defined

Since the COVIS-19 pandemic first began in late December 2019, unprecedented efforts to develop and trial vaccine candidates have led to the emergency use authorization of four vaccines.

However, since a defined correlate of protection (CoP) against COVID-19 did not exist, the efficacy of these vaccines was evaluated in large clinical trials involving participants who were exposed to natural infection with the causative agent – severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – in countries with active epidemics.

Over the last few months, SARS-CoV-2 variants containing mutations have emerged, increasing the virus’s pathogenicity and transmissibility. These mutations may help the virus evade the host immune system.

Determining the efficacy of vaccines in protecting against these variants of concern will now be a high priority for regulatory bodies and vaccine manufacturers in the coming months or perhaps years.

In the absence of a universally accepted CoP against COVID-19, data from Phase III clinical trials and observational studies of the natural history of the disease suggested that neutralizing antibodies (nAbs) are a candidate CoP.

The WHO wants assay results to be harmonized

The measurement of nAbs against SARS-CoV-2 is usually carried out using virus neutralization tests, infectious center assays or micro-neutralization tests, with antibody levels quantified in serum titers for specific percentages of neutralization, the half maximal inhibitory concentration (IC50) or other readouts.

The antibody binding assays are also varied, with readouts expressed using a range of different units such as antibody titer, mean fluorescent intensity units, or chemiluminescent units.

In order to harmonize the results of these assays, the World Health Organization (WHO) has advocated the use of an international standard SARS-CoV-2 immunoglobulin G (IgG) reagent with an assigned unitage as a primary calibrant.

“Internal assay calibrants are assigned a potency relative to the primary calibrant which is expressed in International Units” says Heeney and colleagues. “In this way, antibody levels of samples tested by either neutralization of antibody binding assays can be expressed in International Units and thus immunogenicity and vaccine efficacy data can be compared between different laboratories.”

What did the researchers do?

The researchers used a WHO international standard to benchmark neutralizing antibody responses and binding antibody assays using convalescent sera obtained from patients who were previously hospitalized with COVID-19, National Health Service (NHS) workers who were seropositive for SARS-CoV-2 and seronegative NHS healthcare workers.

Participants had been exposed and infected during the first wave of the pandemic in the UK (between March and October 2020).

The researchers used commercial and non-commercial antibody binding assays and a lateral flow test for the detection of SARS-CoV-2-specific IgG and IgM.  They also used a high-throughput multiplexed particle flow cytometry assay for the SARS-CoV-2 spike protein, nucleocapsid protein and the spike receptor-binding domain (RBD).

The spike RBD mediates the initial stage of the infection process by binding to the host cell receptor angiotensin-converting enzyme 2, while the nucleocapsid protein is involved in packaging viral RNA into new virions.

A multiplex antigen semi-automated immuno-blotting assay was used to measure IgM, IgA and IgG and the team also performed a pseudotyped microneutralization test and electroporation-dependent neutralization assay.

Whenever suitable, the WHO International Standard (NIBSC 20/136) was used to quantify antibody-based parameters in International Units (IU) and in Binding Antibody Units (BAU).

What did they find?

Overall, patients with severe COVID-19 patients had significantly higher levels of SARS-CoV-2-specific neutralizing antibodies (average 1,029 IU/ml) than seropositive healthcare workers with mild or asymptomatic infections (average 379 IU/ml).

The study revealed a strong correlation between nAb levels and spike- and RBD-specific antibody levels.

“This can be potentially very advantageous for assessing protective immunity in clinical trials or in immunosurveillance programs, as evidence supporting the use of nAb as a biomarker of COVID-19 immunity continues to grow,” writes the team.

There was also a strong correlation between intracellular neutralization and nucleocapsid-specific antibody levels.

Studies now need to focus on variants of concern

“We have identified a range of assays and biomarkers of COVID-19 immunity that will be used to define CoP in future studies using serum and plasma samples sequentially collected from these or similar cohorts to those studied here,” says Heeney and colleagues.

The researchers say such studies now need to focus on the SARS-COV-2 variants of concern that have emerged.

“The emergence of these strains with enhanced transmissibility, pathogenicity and antigenicity represents another challenge for vaccine manufacturers and regulators, and developing methods for standardizing assays for comparison of nAb against variants of concern should be a priority,” they conclude.

*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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