Study investigates the spectrum of antibody immunity across several SARS-CoV-2 variants

In a recent study posted to the medRxiv* preprint server, researchers evaluated antibody responses to the spike (S) proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1 strain and variants of concern (VOCs) such as the Alpha, Beta, Gamma, Delta, and Omicron. They also assessed antibody responses to Omicron sub-VOCs such as BA.1 sub-VOC, BA.4/5 sub-VOC, BA.2.75 sub-VOC, and Omicron BA.2.12.1 sub-VOC.

Study: Fully Quantitative Measurements of Differential Antibody Binding to a Spectrum of SARS-CoV-2 Spike Proteins: Wuhan, Alpha, Beta, Gamma, Delta, Omicron BA.1, BA.4, BA.5, BA.2.75 and BA.2.12.1. Image Credit: Kateryna Kon/Shutterstock

Study: Fully Quantitative Measurements of Differential Antibody Binding to a Spectrum of SARS-CoV-2 Spike Proteins: Wuhan, Alpha, Beta, Gamma, Delta, Omicron BA.1, BA.4, BA.5, BA.2.75 and BA.2.12.1. Image Credit: Kateryna Kon/Shutterstock

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The predominance of Omicron sub-VOCs has led to bivalent messenger ribonucleic acid (mRNA) vaccine development to produce antibodies against Wuhan-Hu-1, and the Omicron sub-VOCs, BA.1 and BA.5 by Moderna and Pfizer vaccines, respectively.

The authors previously identified several immune endotypes based on antibody-S protein interactions and reported a universal immune endotype, U(+), exhibiting cross-reactive antibodies to the conserved Achilles epitope. A probable hinge site was identified on SARS-CoV-2 S, essential to bind with the angiotensin-converting enzyme 2 (ACE2) receptor, critical for SARS-CoV-2 entry into the host. Antibodies to the epitope showed cross-reactivity since hinge mutations could lead to complete functional loss.

About the study

In the present study, researchers evaluated humoral responses against Wuhan-Hu-1, Alpha, Beta, Gamma, Delta, and Omicron, including Omicron sub-VOCs such as BA.1 sub-VOC, BA.4/5 sub-VOC, BA.2.75 sub-VOC, and Omicron BA.2.12.1 sub-VOC by performing a fully quantitative endotype analysis using biophotonic multiplexed immunoassays.

The analysis was extended for all aforementioned strains to assess the Achilles epitope conservation for the universal U(+) endotype and the Omicron dropout immunological endotype incidence.

Immunological profiles were assessed for individuals from four cohorts: the pre-pandemic cohort, the Wuhan-Hu-1 strain(+) cohort, two cohorts of vaccinees: one cohort of two-dose Pfizer and/or AZ (AstraZeneca) vaccinees, and another cohort of three-dose vaccinees who received known vaccines, with immunity derived from vaccinations only, or from prior coronavirus disease 2019 (COVID-19).

The biophotonic multiplexed platform used the localized particle-type plasmon resonance concept in an application that sensed anti-SARS-CoV-2 antibodies. The assays were calibrated against NISTmAb (RM8671), a humanized and recombinant immunoglobulin (Ig)G1ĸ with a sequence specific to the respiratory syncytial virus F protein (RSVF). The S protein calibration Ig antibody targeted a site in the S protein subunit 2 (S2) for assessing variant protein integrity.

Seventeen pre-pandemic (before December 2019), polymerase chain reaction (PCR)(-), and 11 positive samples from PCR(+) individuals were obtained. In addition, 26 samples of PCR(+) and anti-SARS-CoV-2 IgG-positive individuals were obtained before June 2020. Samples were also obtained from 96 patients attending clinics. Of these, 13 individuals were one-dose Pfizer or AZ vaccinees, 41 were two-dose Pfizer, Moderna, or AZ vaccinees, who received vaccine doses ≥2.0 weeks before sample collection, and 41 were three-dose vaccinees.

Results

The U(+) endotype was observed with significant humoral responses to all strains tested with an 11% incidence among Wuhan-Hu-1(+) individuals, directly challenging the ‘one-and-done’ immunological claim, while 53% of patients presented with ≥1.0 dropouts. The most prevalent U(±) was a triple dropout, β/γ/δ(-). The universal endotype incidence rates were 22.0% and 54.0% among two-dose vaccinees among three-dose vaccinees, respectively.

The remaining individuals of every cohort showed a wide range of humoral responses, with a few dropout immunological endotypes and the universal endotype with poor humoral responses to ≥1.0 SARS-CoV-2 strains. AZ vaccinees showed U[(1-8)-] dropouts dominated by U(5-), including the Omicron sub-VOCs. In comparison, Pfizer vaccinees showed only U(1-4) comprising a mixture of all SARS-CoV-2 strains. Among three-dose vaccinees, the higher-order dropouts were almost eliminated with no ≥U(5).

The U(±) incidence rate among three-dose vaccinees was 41.0%, indicating individuals with poor sterilizing sera might not eliminate SARS-CoV-2, leading to the persistence of SARS-CoV-2 persistence and mobile-type microcolonies, which might provide pathophysiological pathways for long COVID symptomatology. The pre-vaccine SARS-CoV-2 infection cohort showed median antibody titers for Wuhan-Hu-1 and S protein VOCs, which were greater among two-dose and three-dose vaccinees.

The pre-pandemic, negative control samples were 81.0% negative for anti-S antibodies or unclassified, with two individuals demonstrating a β/γ/δ dropout, indicative of humoral immunity against the Wuhan-Hu-1 strain and the Omicron sub-VOCs, potentially due to a misclassification: the PCR false-positive rate was 4.0%. However, a significantly larger spectrum of antibody responses was observed for Wuhan-Hu-1(+) individuals,two-dose vaccinated and three-dose vaccinated cohorts.

Conclusions

Overall, the study findings showed the humoral immunity spectrum with the universal endotype to the conserved Achilles epitope prevalence across all SARS-CoV-2 strains, pointing towards the development of a universal therapeutic agent or vaccine against SARS-CoV-2.

However, less encouragement is obtained from the universal endotype incidence of 41.0%, indicating that 67% of the population might have an immunological endotype that would not protect. It might even permit SARS-CoV-2 to persist with non-sterilizing sera.

A smartly designed booster vaccination campaign with different vaccines might be needed to break the immunological imprint by selecting heterologous sequences of vaccines, including novel whole-virus and bivalent vaccines.

*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.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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