Pre-existing B-cell immunity against SARS-CoV-2 not detected in pre-pandemic samples

The ongoing spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global public health emergency. SARS-CoV-2 infections cause a wide range of clinical symptoms, from asymptomatic infections to life-threatening acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death.

Study: No substantial pre-existing B cell immunity against SARS-CoV-2 in healthy adults. Image Credit: Kateryna Kon / Shutterstock.com

Background

Innate and adaptive immune responses have a significant impact on disease severity. Pre-existing immunity against SARS-CoV-2 appears to be critical in understanding coronavirus disease 2019 (COVID-19) susceptibility and severity.

SARS-CoV-2 recognition by pre-existing background immunity could potentially minimize disease severity by rapidly developing specific immune responses. Pre-existing T-cell immune responses against SARS-CoV-2, for example, have been identified in unexposed people; however, the prevalence and clinical significance of pre-existing B-cell immunity has yet to be thoroughly explored.

Most studies have only tested SARS-CoV-2 reactivity in serum/plasma or affinity enriched or released immunoglobulin G (IgG) fractions. However, no study to date has not investigated B-Cell receptor (BCR) sequence analysis of SARS-CoV-2-reacting B cells or the characterization of recombinant monoclonal antibodies from uninfected people.

About the study

To this end, a recent iSCIENCE study investigates plasma samples, single B-cells, and monoclonal antibodies isolated from SARS-CoV-2 unexposed individuals to determine the presence of relevant pre-existing SARS-CoV-2 B-cell immunity. The researchers were also interested in conducting a detailed analysis of plasma and IgG fractions.

The study design involved a comprehensive investigation of plasma binding activity of IgG, IgM, and IgA isotypes against diverse beta coronavirus spike (S) proteins including SARS-CoV-2 S1 and S1/S2, HCoV-HKU1 and HCoV-OC43 S enzyme-linked immunosorbent assay (ELISA).

SARS-CoV-2 humoral immunity was thoroughly studied in 150 study participants whose samples were collected prior to the SARS-CoV-2 outbreak. To test activity against SARS CoV-2 and endemic beta coronaviruses, a comprehensive screening of donor plasma and purified IgG samples for binding and neutralization in several functional assays was performed.

The researchers also examined the antibody sequences of 8,174 SARS-CoV-2-reactive B cells at the single-cell level, which was followed by the generation and subsequent analysis of 158 monoclonal antibodies (mAbs). These 158 mAbs were chosen based on the presence of highly similar heavy and/or light chain sequences in pre-pandemic naive B-cell receptor samples.

Study findings

Pre-pandemic plasma samples obtained from 150 and polyclonal IgG exhibited no significant reactivity to SARS-CoV-2 or cross-reactivity to endemic beta coronaviruses in immunological and functional assays assessing SARS-CoV-2 binding and neutralization activity. In fact, only of the tested plasma samples displayed any reactivity to the SARS-CoV-2 S protein.

The binding and neutralization capacity of SARS-CoV-2-reactive B-cells that were isolated from pre-pandemic samples were very low, particularly when compared to COVID-19 convalescent samples. This finding confirmed that pre-pandemic samples collected from healthy adults lacked high-reactive B-cells against SARS-CoV-2.

Similar results were observed following the analysis of mAbs from pre-pandemic samples, which also did not display any relevant binding or cross-reactivity against SARS-CoV-2, HKU-1, or OC43 S proteins. Furthermore, none of the 158 isolated mAbs exhibited any neutralizing activity against SARs-CoV-2 pseudovirus at concentrations of up t0 50 µg/ml.

Implications

Several previous studies have provided evidence that pre-pandemic samples exhibited pre-existing T-cell immunity against SARS-CoV-2. Comparatively, the findings from the current study demonstrate a lack of pre-existing B-cell immunity in unexposed individuals before the start of the COVID-19 pandemic.