Omicron BQ.1 and XBB: Small molecule drugs, bivalent vaccines are still effective, monoclonal antibodies are wiped out

The U.
S.
FDA has approved remdesivir (an RNA-dependent RNA polymerase [RdRp] inhibitor for SARS-CoV-2) for the treatment of Covid-19 in adults and pediatric patients
who are hospitalized or non-hospitalized but at high risk of progression to severe Covid-19.
Emergency use authorizations
were granted to monupivir (RdRp inhibitor) and nematevir (SARS-CoV-2 primary protease inhibitor) in both China and the United States.

The investigators tested the efficacy
of these antivirals by determining the in vitro 50% inhibitory concentration (IC50) of each drug against BQ.
1.
1 and XBB.
Unlike the amino acid sequence of the reference strain Wuhan/Hu-1/2019, the BQ.
1.
1 and XBB isolates underwent P3395H substitution
in their main protease.
BQ.
1.
1 and XBB isolates also had 2 (Y264H and P314L) and 3 (P314L, M659I, and G662S) amino acid substitutions
in their RdRp.
The sensitivity of BQ.
1.
1 and XBB to the three compounds was similar
to that of the original strain.
For the BQ.
1.
1 subbranch, remdesivir IC50 values decreased to 0.
6x, while monupivir and nematevir rose to 1.
1 and 1.
2 times
, respectively.
For the XBB subbranch, the IC50 value of remdesivir decreased to 0.
8-fold, monupivir to 0.
5-fold, and nematevir to 1.
3-fold (Figure 1B).

These results showed that remdesivir, monupivir, and nematevir were effective against BQ.
1.
1 and XBB in vitro
.

Figure 1 In vitro efficacy of therapeutic monoclonal antibodies and antiviral drugs on the omicron subbranch.

Data from this study suggest that the omicron subclade BQ.
1.
1 and XBB have a stronger
immune evasion capacity than earlier omicron subvariants, including BA.
5 and BA.
2.
Persistent mutations in the omicron strain have reinforced the demand
for new therapeutic monoclonal antibodies to Covid-19.

Japanese scholars evaluated the efficacy
of therapeutic monoclonal antibodies against BQ.
1.
1 and XBB clinical isolates.
To check the responsiveness of monoclonal antibodies to these subbranches, the researchers determined the FRNT50 titer of monoclonal antibodies using a live virus neutralization assay
.
Of the 5 monoclonal antibodies and 3 antibody combinations selected by the authors that had been approved to treat the original strain and the early variant of the new crown, none of them were effective in neutralizing BQ.
1.
1 or XBB.

These results suggest that these monoclonal antibodies may not be clinically effective for
BQ.
1.
1 or XBB.

BQ.
1 is a sixth-generation subvariant strain produced by omicron BA.
5 mutated during transmission
.
BQ.
1.
1 is the first generation subbranch
of BQ.
1.
XBB is generated
by recombination of two different BA.
2 subvariants.
Compared to BA.
5, BQ.
1.
1 has 3 more amino acid substitutions in the receptor-binding domain of its spike protein (S); compared to BA.
2, XBB has 9 more amino acid substitutions
in its receptor-binding domain.
This spike protein is the primary target of Covid-19 vaccines and therapeutic monoclonal antibodies, so these two subvariants may be more immune evasive than BA.
5 and BA.
2
.

Japanese scholars evaluated the neutralization ability of plasma antibodies against BQ.
1 and XBB clinical isolates in three different populations: the cohort of three doses of monovalent mRNA vaccine BNT162b2 (Pfizer) or mRNA-1273 (Moderna) or a combination of both (180~189 days after the third dose of vaccine; n=20）； Cohort of four doses of monovalent mRNA vaccine BNT162b2 or mRNA-1273, or both (33~57 days after the fourth dose; n=20）； and cohorts receiving three doses of monovalent BNT162b2 or mRNA-1273 vaccine before BA.
2 breakthrough infection (29~89 days post-infection; n=10）
。

The investigators used a live virus neutralization test to determine FRNT50
in plasma samples against BA.
2, BA.
5, BQ.
1.
1, and XBB.
In the cohort of three-dose mRNA vaccine, the vast majority of samples had FRNT50 values below the detection limit
for BQ.
1.
1 or XBB.
To calculate the geometric mean titer of each group of antibodies, the investigators assigned a value of 10 to samples with FRNT50
values below the detection limit.
The geometric mean titers of FRNT50 for BQ.
1.
1 and XBB were 21.
1-fold and 21.
6-fold
lower than for the original strain, respectively.
In addition, the geometric mean titer for BQ.
1.
1 and XBB is 1.
7 and 2.
6 times
lower than for BA.
5 and BA.
2, respectively.
A cohort of four doses of mRNA vaccine received similar results
.

In contrast, samples from most breakthrough-infected BA.
2 vaccinated people neutralized BQ.
1.
1 and XBB; however, the geometric mean titer of FRNT50 against BQ.
1.
1 and XBB was 35.
2 and 61.
7 times lower than that against the original strain and 4.
9 and 15.
1 times
lower than for BA.
5 and BA.
2, respectively.

These data suggest that the omicron subclade BQ.
1.
1 and XBB are effective in evading current humoral immunity
induced by mRNA vaccines or natural infection.
BQ.
1.
1 and XBB clinical isolates have higher immune evasion capabilities
than earlier omicron subvariants, including BA.
5 and BA.
2.

The United States has now approved a Covid-19 bivalent vaccine
against the original spike protein and omicron BA.
5 spike protein.
Serum samples from participants who had received one or two monovalent vaccine boosters or bivalent vaccine boosters were tested to determine the neutralization efficiency
of different booster vaccines against wild-type viruses and omicron subvariant BA.
1, BA.
5, BA.
2.
75.
2, BQ.
1.
1 and XBB.

The study also included three cohorts: 7~28 days after a single booster dose of monovalent vaccine (n=12), 6~57 days after two booster doses of monovalent vaccine (n=11), and 16~42 days after booster dose of bivalent vaccine (n=12).

The method was also to quantify the differences
in neutralizing antibody responses between the three cohorts by comparing the geometric mean titer (GMT) of the neutralizing antibody against the omicron subvariant and FRNT50 against the neutralizing antibody against the original strain (WA1/2020).
If the serum sample GMT falls below the detection limit (1:20), FRNT50 is assigned a value of 10
.

In simple terms, the neutralizing activity for all omicron subvariants was lower than for WA1/2020 in all three cohorts; Neutralization activity is lowest for XBB subbranches (Figure 2).

In the cohort with intensive bivalent vaccine against BA.
5, neutralizing activity against all omicron subvariants was superior to the other two cohorts compared to neutralizing activity against WA1/2020 (Figure 2C).

Figure 2 Neutralization response
against WA1/2020 strain and omicron subvariant.

The figures show the neutralizing activity
of the WA1/2020 strain and the omicron subvariant BA.
1, BA.
5, BA.
2.
75.
2, BQ.
1.
1 and XBB of 12 participants receiving monovalent vaccine twice (Figure C) against the WA1/2020 strain of SARS-CoV-2, the omicron subvariant strain BA.
1, BA.
5, BA.
2.
75.
2, BQ.
1.
1 and XBB 。 The geometric mean titer of FRNT50 for neutralizing antibodies against WA1/2020 strains and omicron subbranched strains is shown at the top of each plot, as well as neutralizing GMT ratios of WA1/2020 strains to omicron subbranched
strains.
The connecting lines between variants represent matched serum samples
.
The horizontal dashed line represents the limit of detection (FRNT50GMT 20).

The red lines in Figures B and C represent participants who reported having been infected with SARS-CoV-2, and the dotted lines in Figure C represent participants whose patient received two doses of monovalent vaccine prior to booster bivalent vaccine
.
The colored bars represent the FRNT50 GMT of the participants in the cohort, and the I bars represent the 95% confidence interval, which is not multiple-adjusted
.
LOD represents the limit of detection, NA is not applicable
.

People who received a single or double booster dose of monovalent Covid-19 vaccine had much lower neutralizing activity against omicron subvariant strains (particularly BA.
2.
75.
2, BQ.
1.
1 and XBB) than against WA1/2020
strains 。 The neutralization activity of the two-booster monovalent vaccine cohort and the booster-dose bivalent vaccine cohort for BA.
5 was similar for WA1/2020, but the neutralization activity of the fortified bivalent vaccine cohort was better than that of all omicron subvariants (particularly BA.
2.
75.
2, BQ.
1.
1 and XBB) than those with
single or two booster monovalent vaccines.
These data suggest that booster bivalent vaccines have an overall in vitro neutralizing effect
on BQ.
1.
1 and XBB.

References