Anti-Omicron antibodies are induced by hypermutation by the ancestral BNT162b2 COVID vaccine

*Important Notices: Bio Rxiv We publish a non-peer-reviewed, preliminary scientific report and should not be taken as conclusive, to guide clinical practice/health-related actions, or to be treated as established information.

South Korean scientists analyzed the B-cell receptor repertoire induced by an mRNA-based coronavirus disease 2019 (COVID-19) vaccine and found that somatic hypermutation of the B-cell receptor heavy chain increases specificity for unexposed antigens. was found to be the cause of the expansion of

This research is currently Bio Rxiv* Preprint Server.

study: Ancestral vaccine induces anti-omicron antibodies by hypermutationImage Credit: Lightspring/Shutterstock

Background

During the entire course of the COVID-19 pandemic, the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone many mutations.Some of these mutations, particularly those located in the viral receptor binding domain (RBD) spike proteinwhich provided selective advantages and led to the emergence of new virus variants with improved fitness.

Among many variants, the recently emerged omicron has acquired 15 mutations in its spike RBD, greatly enhancing the virus’ ability to evade immune systems. His COVID-19 vaccine, developed against the original Wuhan strain, shows significantly reduced ability to neutralize the Omicron variant.

Vaccines significantly improved due to global rollout of booster vaccination Effectiveness For omicron, it has been observed in the general population. However, it remains unclear how repeated exposure to the ancestral spike protein by booster vaccination is associated with increased production of antiomicrons. Neutralizing antibody.

The current study chronologically analyzed the B-cell receptor (BCR) repertoire of individuals who received three doses of the Pfizer/BioNTech-developed mRNA-based COVID-19 vaccine. They are primarily intended to track the development of anti-ohmicon neutralizing antibodies.

research design

The study included a total of 41 HCWs who received two doses of Pfizer’s COVID-19 vaccine three weeks apart, with a third dose approximately nine months after the first dose. I was.

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

Characterization of Omicron RBD-specific antibody clones

Scientists in silico Chronological BCR repertoire using next-generation sequencing and comparing the frequency of BCR heavy chain clonotypes listed in the CoV-Ab Dab17 database that bind to the SARS-CoV-2 spike protein.

Five Omicron-specific neutralizing BCR heavy chain clonotypes were chronologically analyzed in selected participants before and after the third vaccination.

The findings revealed that all five BCR heavy chain clonotypes responded to ancestral RBD before the third dose. However, the two BCR heavy chain clonotypes showed similar levels of reactivity to the omicron RBD. Three other clonotypes showed minimal or reduced reactivity to omicron RBD before the third dose.

After the third dose, we observed a significant increase in the number of somatic hypermutations in the BCR heavy chain clonotype, which greatly increased its affinity for the omicron RBD. A significant increase in heavy chain complementarity determining region 3 (CDR3) sequence diversity was also observed after the third dose. This finding further justifies the expansion of BCR specificity to the omicron RBD by booster vaccination.

Forty-six percent of participants had the official clonotypes of immunoglobulin G heavy chain variable region 3-53/3-66 (IGHV3-53/3-66) and immunoglobulin heavy binding 6 (IGHJ6) RBD antibodies and show simultaneous reactivity to Omicrons. RBD found. Somatic hypermutation and associated heavy chain CDR3 diversification were responsible for the double reactivity.

Significance of research

In this study, we describe that a third dose of the Pfizer COVID-19 vaccine encoding an ancestral spike RBD causes the accumulation of somatic hypermutation in ancestral RBD-specific antibody clones. Moreover, these somatic hypermutations cause responsiveness of some of these clones to the Omicron RBD, resulting in a significant induction of anti-Omicron RBD antibody levels in the blood.

As scientists have mentioned, BCR-specific somatic mutational spread is a counter-defensive mechanism against immune escape of viral mutants.

*Important Notices: Bio Rxiv We publish a non-peer-reviewed, preliminary scientific report and should not be taken as conclusive, to guide clinical practice/health-related actions, or to be treated as established information.