Omicron antibodies are induced by hypermutation with the BNT162b2 COVID progenitor vaccine

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*Important note: bioRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, directing clinical practice/health-related behaviour, or treated as hard information.

Scientists from the Republic of Korea analyzed the B cell receptor repertoire generated by the mRNA-based coronavirus vaccine 2019 (COVID-19) and found that hypermutation of somatic mutations in the B cell receptor heavy chain is responsible for extending its specificity to unexposed antigens.

The study is currently available at bioRxiv* Prepress server.

Study: An ancestral vaccine induces Omicron antibodies by hypermutation.  Image credit: Lightspring/ShutterstockStady: Progenitor vaccine induces Omicron antibodies by hypermutation. Image credit: Lightspring/Shutterstock

background

During the entire course of the COVID-19 pandemic, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome has undergone many mutations. Some of these are mutations, particularly those in the virus receptor-binding domain Spike proteinprovided a selective advantage, resulting in novel viral variants with improved fitness.

Among several variants, the recently emerged ometron acquired 15 RBD mutations, which greatly increased the immune evasion ability of the virus. COVID-19 vaccines developed against the original Wuhan strain showed a significantly reduced ability to neutralize the Omicron variant.

With the global spread of the booster vaccine, a significant improvement in the vaccine effectiveness against omicron has been observed in the general population. However, it remains unclear how repeated exposure to the spike progenitor protein through booster immunization is associated with increased anti-omericon production. neutralizing antibodies.

In the current study, the scientists analyzed a time-sequence of the B cell receptor (BCR) of individuals vaccinated with three doses of an mRNA-based COVID-19 vaccine developed by Pfizer/BioNTech. They mainly aimed to track the evolution of Omron-neutralizing antibodies.

study design

The study was conducted on a total of 41 healthcare workers who received two doses of the Pfizer COVID-19 vaccine three weeks apart and the third dose approximately nine months after the first dose.

Peripheral blood samples were collected from the participants at six time points, that is, before vaccination, three times after each dose, and twice between the second and third doses. Blood samples were analyzed to measure levels of antibodies against the ancestral spike RBD and the omicron spike RBD.

Characterization of an Omikron RBD-specific antibody clone

Scientists selected six vaccine recipients through reconstitution in silico BCR chronological repertoire using next generation sequencing and frequency comparison of BCR heavy chain clone patterns included in the CoV-Ab Dab17 database that binds the SARS-CoV-2 spike protein.

In selected participants, they analyzed the chronology of five Omicron-specific heavy-chain clone phenotypes before and after the third vaccine dose.

The results revealed that all five BCR heavy chain clones interact with the ancestral RBD before the third dose. However, two BCR heavy chain clone haplotypes showed a similar level of interaction with the omicron RBD. The other three clones showed little or reduced reactivity to omicron RBD before the third dose.

A significant increase in the number of excessive somatic mutations in heavy-chain BCR clone phenotypes was observed after the third dose, significantly increasing their affinity for omicron RBD. A significant increase in complement heavy chain region 3 (CDR3) sequence diversity was also observed after the third dose. This result also justifies the expansion of BCR specificity for omicron RBD by booster vaccination.

In 46% of the participants, the general immunoglobulin G heavy chain variant 3-53/3-66 (IGHV3-53/3-66) and immunoglobulin heavy chain 6 (IGHJ6) RBD antibody with concomitant reaction to progenitors and ometrons were Find RBDs. Excessive somatic transformations and diversification associated with the CDR3 heavy chain were responsible for the dual interaction.

Significance study

The study describes that a third dose of a Pfizer COVID-19 vaccine encoding an ancestral RBD spike leads to the accumulation of hyper-transformations in clones of RBD-specific antibodies. Moreover, these hyper-somatic transductions cause some of these clones to react toward omicron RBD, leading to a significant induction of omicron RBD antibody levels in the blood.

As reported by the scientists, the somatic mutation-induced expansion of BCR specificity is a protective countermechanism against immune escape of virus variants.

*Important note: bioRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, directing clinical practice/health-related behaviour, or treated as hard information.

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