A panel of 482 human monoclonal antibodies’ ability to neutralise Omicron BA.4 and BA.5

The variations of SARS-CoV-2 Omicron sublineages BA.4 and BA.5 that are currently prevalent worldwide. They had higher human angiotensin-converting enzyme 2 (hACE2) binding affinities than other Omicron sub-variants due to the absence of the G496S mutation in their S protein. They have also developed to block the host’s inherent immunological responses. In order to develop strategies to put an end to BA.4/relentless BA.5’s rampage, it is essential to comprehend the methods they use to evade innate immunity and vaccine-induced immunity.

Concerning the study
The current investigation assessed the neutralising activity of a panel of 482 human monoclonal antibodies (mAbs) against the BA.4 and BA.5 sub-variants of the original Wuhan-Hu1 SARS-CoV-2 strain.

To create the study mAb panel, they used sera from three different cohorts: I SARS-CoV-2 seronegative subjects who received two doses of any messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccine (SN2); ii) SARS-CoV-2 seronegative subjects who received three doses of any mRNA vaccine (SN3); and iii) SARS-CoV-2 seropositive subjects who (SP2).

A cytopathic effect-based microneutralization assay (CPE-MN) was performed by the researchers to evaluate the mAb panel’s ability to neutralise BA.4 and BA.5 antibodies.

Study results

Omicron BA.4 and BA.5 subvariants were not neutralised by any of the 52 antibodies from the SN2 cohort, however the authors did observe some limited cross-protection against BA.1 and BA.2. On the other hand, Omicron BA.4 and BA.5 were cross-neutralized by 14.6% and 14.1% of the 206 nAbs from the SN3 cohort, respectively. Similar to this, BA.4 and BA.5 subvariants were cross-neutralized by 15.5% and 14.6% of the 224 nAbs obtained from SP2, respectively. It is noteworthy that none of the tested nAbs exhibited highly effective neutralising activity against all Omicron sublineages. Only LY171 CoV1404 or Bebtelovimab shown high neutralising potency against all Omicron sublineages among the therapeutic mAbs. Its 100% inhibitory concentration (IC100) values against Omicron BA.1, BA.2, BA.4, and BA.5 were 11.1, 15.6, 44.2, and 62.5 ng ml-1, respectively.

Additionally, the analysis of the study’s data revealed startling variations in the B cell germline patterns that underlie these similar reactions. A three-dose course of an mRNA vaccination primarily improved Class I and II nAbs that target the receptor-binding domain (RBD) and demonstrated a more clonal B cell response. Five B cell germlines (IGHV1-58; IGHJ3-1; IGHV1-69; IGHJ3-1; IGHV1-69; IGHJ4-1; and IGHV3-66; IGHJ6-1) made up the B cell response, and they accounted for about 60% of all Omicron cross-neutralizing antibodies. IGHV1-69: IGHJ4-1 and IGHV3-66: IGHJ4-1, two of the five B cell germlines that code for cross-neutralizing nAbs in the SN3 cohort, were surprisingly present in the SN2 cohort as well, although they here did not exhibit any functional activity against Omicron sub-variants.


The study’s findings as a whole showed that a third dose of mRNA vaccination (booster) improved B cell affinity maturation of particular germlines, their multiplication, and ensuing production of cross-reactive nAbs. B cell responses for hybrid immunity were significantly more varied and favoured RBD-directed Class III and N-terminal domain (NTD)-targeting nAbs. Therefore, a response against the Omicron sub-variants was only produced by three B cell germlines, notably IGHV1-24:IGHJ6-1, IGHV1-58:IGHJ3-1, and IGHV2-5:IGHJ4-1, which together account for about 31% of the total nAb response.

Regarding the processes of antigen presentation during the immune response to SARS-CoV-2 infection and vaccination, the study raised some concerns. The growth of several B cell germlines, which led to the production of nAbs that targeted various epitopes on the SARS-CoV-2 S protein, was seen by the authors as a result of homologous mRNA vaccination and SARS-CoV-2 infection.

It is interesting to observe that following SARS-CoV-2 infection and immunisation, various immune cell types exhibit antigens in various ways. Therefore, the mechanics of the induced innate immune response are jointly governed by several cell types expressing the antigen, the stabilisation of the S protein in its prefusion shape, other viral components, and the inflammatory milieu of the cell. Next-generation COVID-19 medicines and vaccines may be created with the aid of this special information.

*Notice: BioRxiv publishes preliminary scientific studies that have not been peer review and should not be taken as established knowledge, should not be used to direct clinical practise or health-related behaviour, and should not be regarded as definitive.

Journal reference:
Andreano, E. et al. (2022) “mRNA vaccines and hybrid immunity use different B cell germlines to neutralize Omicron BA.4 and BA.5”. bioRxiv. doi: 10.1101/2022.08.04.502828. https://www.biorxiv.org/content/10.1101/2022.08.04.502828v1

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