# Mass‐Standardised Differential Antibody Binding to a Spectrum of SARS‐CoV‐2 Variant Spike Proteins: Wuhan, Alpha, Beta, Gamma, Delta, Omicron BA.1, BA.4/5, BA.2.75 and BA.2.12.1 Variants—Antibody Immunity Endotypes

## TL;DR

This study compares antibody responses to different SARS-CoV-2 variants and finds that triple vaccination boosts broad immunity, while some people may remain at risk for persistent infection.

## Contribution

The study introduces a mass-standardized method to quantify differential antibody binding across multiple SARS-CoV-2 variants and identifies distinct immunity endotypes.

## Key findings

- Triple vaccination increases U(+) immunity profiles to 54%, showing broad protection against variants.
- Up to 13% of individuals have very low antibody concentrations across all variants, potentially risking persistent infection.
- U(+) antibody responses preferentially target the S1 region of the spike protein.

## Abstract

A fully mass‐standardised quantitative comparative analysis of the differential antibody binding to spike variant proteins to SARS‐CoV‐2 has been performed for the variants: Wuhan, Alpha, Beta, Gamma, Delta and the Omicron variants BA.1, BA.2.12.1, BA.2.75, BA.4 and BA.5. Evolution of immunity through five patient cohorts (n = 148 in total) was studied including pre‐pandemic, first infection, first vaccine, second vaccine and triple‐vaccinated cohorts. A population of immunity endotypes has been observed and is classified against a recovery antibody threshold, with concentrations below this threshold being regarded as a ‘dropout’: U(+) showing protection to all variants; U(±) with single, double, triple and further dropout endotypes; and U(−) with all variant concentrations being under the threshold. The U(+) incidence rises significantly following multiple rounds of vaccination reaching an (n = 41) incidence of 54% (95% CI 39%–68%) suggesting between half and three‐quarters of the population have universal variant vaccine antibody protection. The U(+) epitopes are targeted preferentially to the S1 region. U(±), with at least one dropout, has an incidence of 42% (95% CI 28%–57%), an immunity gap. Further, a U(−) sub‐cohort of the population up to 13% does not make antibodies above the threshold and may not have a sterilising serum leading to persistent virus and a risk of Long COVID.

Fully quantitative, mass‐standardised, antibody responses to ten SARS‐CoV‐2 variants show significant variation in immunity profiles or endotypes. The incidence of the complete response to all variants is significantly improved after three vaccinations. Up to 13% of profiles are very low concentrations for all variants and point to risks in viral persistence such as long COVID.