Improved monoclonal antibody neutralization for Omicron
sublineages BA.2.75, BF.7 and BQ.1
Authors: Ekant Tamboli, Lekha Salsekar, Shefali Rahangdale, *Krishna
Khairnar
Author Affiliation: Environmental Virology Cell (EVC), Council of
Scientific and Industrial Research-National Environmental Engineering
Research Institute (CSIR-NEERI), Nagpur, India.
*Corresponding author: Correspondence to Krishna Khairnar e-mail:
k_khairnar@neeri.res.in
ABSTRACT: The mortality rate due to COVID-19 in immunocompromised cases
is considerably high. Monoclonal antibody (mAb) therapy is essential in
managing SARS-CoV-2 infection, especially in immunocompromised cases.
The mutation in the spike protein RBD region of the SARS-CoV-2 leads to
the substitution of amino acids resulting in an altered ACE2 binding
affinity. The mAbs must be tested in-vitro using standard neutralisation
assays designed against emerging SARS-CoV-2 variants to estimate the mAb
therapy efficacy. Based on already available data on the mAb efficacy
for known SARS-CoV-2 variants, it is plausible to draw inferences for
other closely related SARS-CoV-2 variants in circulation owing to the
similar spike protein RBD amino acid sequence. In this article, we have
attempted to analyse the data of mAb efficacy tested against SARS-CoV-2
variants and extrapolate on other emerging omicron sublineages like
BA.2.75, BF.7 and BQ.1.
INTRODUCTION: In December 2019, SARS-CoV-2 emerged as the etiological
agent for the COVID-19 pandemic and continued to evolve. Various
subvariant of SARS-CoV-2 B.1.1.529 (Omicron) emerged and dominated the
pandemic since November 2021.1 Some omicron
subvariants have significantly dominated globally, like BA.1, BA.2,
BA.2.75, BA.2.75.2, BA.4.6, BA.4/BA.5, BF.7, XBB, XBB.1, BQ.1, BQ.1.1,
CH.1.1 and BJ.1. The international spread of SARS-CoV-2 lineages of
concern can be tracked by accessing daily reports available at the
website cov-lineage.2 The report revealed that VOCs
like BA.2.75, BQ.1 and BF.7 had spread significantly across the globe.
BA.2.75 has been reported from India 70.0%, Australia 3.0%, United
Kingdom (UK) 3.0%, Canada 3.0% and United States of America (USA)
6.0%; BQ.1 has been reported from USA 56.0%, Canada 7.0%, UK 6.0%,
France 4.0% and Sweden 4.0%; BF.7 has been reported from USA 16.0%,
Germany 17.0%, Denmark 10.0%, Belgium 6.0% and France 10.0%.
RESULTS & DISCUSSION: We observed that the spike protein RBD region’s
amino acid sequence for dominant omicron subvariants like BA.2.75, BQ.1
and BF.7 had significant similarities to the already studied BA.2.75.2,
BQ.1.1 and BA.4 / BA.5, respectively (Figure A). Compared with
subvariant BA.2.75, BA.2.75.2 contains three additional mutations,
R346T, G482S and F486S, in the spike protein RBD region (Figure A).
Compared with subvariant BQ.1, BQ.1.1 contains one additional mutation,
R346T, in the spike protein RBD region (Figure A). Compared with
subvariant BA.4/BA.5, BF.7 contains one additional mutation, R346T, in
the spike protein RBD region (Figure A). The fact that the two
dominating subvariant BA.2.75 and BQ.1 have no mutations at the R346
residue raises optimism that monoclonal antibodies may show improved
efficacy. Earlier studies have shown that the efficacy of several
therapeutic monoclonal antibodies (mAbs) was impaired because of
mutation at the position R346K in an Omicron subvariant
BA.1.1.3,4
Various reports are indicating higher COVID-19 mortality rates amongst
immunocompromised patients. The morbidity and mortality weekly report
(MMWR) published by CDC in July 2022 shows that the mortality rates of
vaccinated and unvaccinated immunocompromised patients were reported to
be 16.5% and 12.9%.5 Another report from France that
studied critically ill patients showed a mortality rate of 46.9% for
Omicron infected immunocompromised patients compared to
non-immunocompromised patients with a mortality rate of
26.2%.6 A report from the UK by Turtle et al.
revealed the mortality rate of immunocompromised hospitalised patients
as 36% and 19% in the first COVID-19 wave and the fourth Omicron wave,
respectively.7 Belsky et al. analysed a mortality rate
of 23.2% amongst COVID-19 patients who were immunocompromised and had
undergone a solid organ transplant. Amongst immunocompromised cases in
pediatric cancer patients and adult cancer patients, the mortality rate
was observed to be 10.9% and 28.1%, respectively.8The rate of mortality is unusually high in the immunocompromised cases
who have comorbidities; in such groups, the role of monoclonal antibody
therapy is indispensable. The study conducted by Arora et al. emphasises
the role of mAbs in managing SARS-CoV-2, especially in immunocompromised
cases.9
As per the findings of the study conducted by Arora et al., it was
revealed that all mAbs included in the study had shown efficient
neutralisation against the B.1 pseudovirus particle (pp) possessing
wild-type S protein RBD region.9 The study establishes
that the wild-type S protein RBD region is strongly correlated with the
efficient neutralization of the virus by the mAbs. Considering this
strong correlation, we propose extrapolating the findings of the mAb
neutralisation assay for other SARS-CoV-2 omicron sublineages, which
have a similar S protein RBD region amino acid sequence. In the study of
Arora et al, bebtelovimab mAb efficiently neutralised the BA.2.75.2pp
and Regdanvimab, and Sotrovimab mAbs poorly neutralised the BA.2.75.2pp.
The S protein RBD region amino acid sequence for BA.2.75.2 is similar to
BA.2.75, except at positions 346, 482 and 486 where BA.2.75 possesses
wild-type amino acid (Figure A). This may imply that the wild-type at
position 346 may impart efficient neutralisation against BA.2.75 when
bebtelovimab is used. The wild-type at positions 486 and 346 may improve
the neutralisation efficacy from poor to moderate against BA.2.75 when
Regdanvimab and Sotrovimab are used, respectively. In the study of Arora
et al, cilgavimab and bebtelovimab mAbs efficiently neutralised the
BA.4/BA.5pp. Imdevimab mAb and Cilgavimab-Tixagevimab (cocktail mAbs)
moderately neutralised BA.4/BA.5pp. The S protein RBD region amino acid
sequence for BA.4/BA.5 is similar to BF.7, except at amino acid position
346, where BF.7 possesses a mutation R346T (Figure A). This may imply
that the mutation at position R346T may reduce the neutralisation
efficacy from efficient to moderate against BF.7 when bebtelomivab and
cilgavimab are used. Similarly, the mutation at position R346T may also
reduce the neutralisation efficacy from moderate to poor against BF.7
when imdevimab, and Cilgavimab-Tixagevimab (cocktail mAbs) are used. In
the study of Arora et al, the BQ.1.1pp were not neutralised by any mAbs;
all mAb neutralisation assays had EC50 values >50,000ng/ml.
The S protein RBD region amino acid sequence for BQ.1.1 is similar to
BQ.1, except at position 346, where BQ.1 possesses wild-type amino acid
(Figure A). This may imply that no mutation at position 346 may improve
the neutralisation efficacy for BQ.1.
A comparison of globally prevalent Omicron sublineages was performed for
their respective RBD residues interacting with ACE2 against mAb EC50
values (Figure B). In total, 17 RBD residues that interact with ACE2
have been identified, out of which 8 positions had mutations, and 9
positions had no mutations across 14 Omicron sublineages. The analysis
revealed that there are 8 positions of RBD residues with no mutations
that interact with ACE2, which may continue to be efficiently targeted
by mAbs. We further analysed the recent data reported by Arora et al
which revealed that two mAbs, Sotrovimab and Romlusevimab, did not
target any RBD residues interacting with ACE2 (Figure B). As per the
supplementary table titled ‘antibody information’ in the article of
Arora et al, it is declared under the mode of action that Sotrovimab-
abrogates S protein driven entry at a post attachment step and
Romlusevimab- abrogates S protein/ACE2 interaction. The information in
the supplementary table and Figure S1 does not corroborate for
Romlusevimab as no RBD residues interacting with ACE2 are represented in
Figure S1. As per the report, even at the highest concentration
Romlusevimab (IC50 >200 nM) did not compete with ACE2 for
binding to RBD, implying that Romlusevimab does not block RBD residues
interacting with ACE2.10 This indicates that the
information in the supplementary table of the article published by Arora
et al, the proposed mode of action of Romlusevimab does not corroborate
with the finding of our analysis.
The comparative analysis of mAb interacting at mutation positions in RBD
revealed a strong correlation against neutralization assay for all mAbs
except for Bamlanivimab, Etesevimab and Bebtelovimab which showed no
correlation. The detailed correlation between the monoclonal antibody
neutralisation assay and the mutation at the position in the spike
protein RBD region is depicted in the Table.
METHOD: The neutralization efficacy of monoclonal antibodies against
omicron subvariants was assessed by comparing the amino acid
substitutions in the RBD region of SARS-CoV-2. The information on
SARS-CoV-2 omicron subvariants that have significantly dominated
globally was obtained from the emerging variants tool in Global
Initiative on Sharing All Influenza Data (GISAID) (https://gisaid.org/).
The data on the international spread of SARS-CoV-2 lineages were
obtained from Cov-Lineages (https://cov-lineages.org). The information
on the mutations leading to the amino acid substitution in the RBD
region of the spike protein of SARS-CoV-2 lineages was obtained from
outbreak.info SARS-CoV-2 data explorer (https://outbreak.info) and
CoVariants (https://covariants.org). The information on the target and
the mode of action for the SARS-CoV-2 monoclonal antibodies like
Casirivimab11-13, Imdevimab11-13,
Bamlanivimab13-16, Etesevimab13-16,
Cilgavimab13,17-19,
Tixagevimab13,17-19,
Amubarvimab13,20,21,
Romlusevimab13,20,21,
Adintrevimab22, Regdanvimab13,23,24,
Bebtelovimab13,17,25-29 and
Sotrovimab13,27,28,30,31 was summarised in the Figure.
The qualitative data analysis was performed using google spreadsheets.
ACKNOWLEDGMENTS:
This work was supported and funded by CSIR-NEERI, Nagpur.
DECLARATION OF INTERESTS:
The authors declare no competing interests.
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