Harmonization of Multiple SARS-CoV-2 Reference Materials Using the WHO IS (NIBSC 20/136): Results and Implications

Abstract

BackgroundThere is an urgent need for harmonization between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology platforms and assays prior to defining appropriate correlates of protection and as well inform the development of new rapid diagnostic tests that can be used for serosurveillance as new variants of concern (VOC) emerge. We compared multiple SARS-CoV-2 serology reference materials to the WHO International Standard (WHO IS) to determine their utility as secondary standards, using an international network of laboratories with high-throughput quantitative serology assays. This enabled the comparison of quantitative results between multiple serology platforms.MethodsBetween April and December 2020, 13 well-characterized and validated SARS-CoV-2 serology reference materials were recruited from six different providers to qualify as secondary standards to the WHO IS. All the samples were tested in parallel with the National Institute for Biological Standards and Control (NIBSC) 20/136 and parallel-line assays were used to calculate the relevant potency and binding antibody units.ResultsAll the samples saw varying levels of concordance between diagnostic methods at specific antigen–antibody combinations. Seven of the 12 candidate materials had high concordance for the spike-immunoglobulin G (IgG) analyte [percent coefficient of variation (%CV) between 5 and 44%].ConclusionDespite some concordance between laboratories, qualification of secondary materials to the WHO IS using arbitrary international units or binding antibody units per milliliter (BAU/ml) does not provide any benefit to the reference materials overall, due to the lack of consistent agreeable international unit (IU) or BAU/ml conversions between laboratories. Secondary standards should be qualified to well-characterized reference materials, such as the WHO IS, using serology assays that are similar to the ones used for the original characterization of the WHO IS.

An omicron-specific neutralizing antibody test predicts neutralizing activity against XBB 1.5

“…In the early days of the pandemic, lack of standardization among SARS-CoV-2 antibody assays was a challenge to the successful implementation of antibody testing strategies for vaccine development and clinical monitoring of immune responses to infection and vaccination ( 24 ). In Dec 2020, the WHO Expert Committee on Biological Standardization (ECBS) established the 1st WHO International Standard (IS) for anti-SARS-CoV-2 immunoglobulin (NIBSC code 20/136) ( 25 ).…”

Validation and Suitability Assessment of Multiplex Mesoscale Discovery Immunogenicity Assay for Establishing Serological Signatures Using Vaccinated, Non-vaccinated and Breakthrough SARS-COV-2 Infected Cases

“…The method's selectivity was evaluated using three human serum matrices: (i) matrix 1-Sera from healthy volunteers (samples 10-15), (ii) matrix 2-haemolytic and lipemic matrix (samples [16][17], and (iii) matrix 3-NIBSC negative sample (sample 18), and (iv) antibody-depleted human sera (sample 19) as mentioned in Table 1. These matrices are representative of 10 negative or low concentration sera.…”

“…The study involves use of a sera samples collected during 2021-22, following infection and/or vaccination. The evaluation also covered studies with NIBSC reference standard (NIBSC 20/268), WHO reference panel for anti-SARS-CoV-2 immunoglobulin 16 . Assay demonstrated establishment of distinct serological signatures in different groups and thereby establishing the usefulness of multiplex assays in generation of robust data on seropositivity which will be useful during serosurveillance studies.…”

Serodynamics: a review of methods for epidemiological inference using serological data

“…For example, the same sample run on the same assay at different labs can lead to different results [66]; repeated freeze-thaw or poor storage conditions might lead to sample degradation [67]; different strains or stocks of the same antigen might perform differently in an otherwise identical assay [68,69]. Much of the laboratory pipeline and international guidelines aims to standardize and minimize the impact of these sources of variation (e.g., by normalizing measurements using positive controls or other replicates in the same batch) [70][71][72]. Although controls and metadata are usually available to disentangle sources of variation in the measurement process, they may be lost or unavailable to the person analyzing the data.…”