Spike 346 Mutations Emerging In Many New Omicron Variants And Sub-lineages Is Helping SARS-CoV-2 To Escape Neutralization By All Known Antibodies!
A new study by researchers from Peking University, Beijing-China has found that the spike 346 mutations found in almost all of the new emerging Omicron variants and sub-lineages are helping the SARS-CoV-2 virus escape neuralization by almost all known antibodies!
The scientists warn that the SARS-CoV-2 BA.2, BA.4 and BA.5 lineages that have been the dominant strains in most regions worldwide and are continuously gaining mutations in the receptor-binding domain.
A number of BA.4 and BA.5 subvariants with Arg346 mutations in the spike glycoprotein have been identified in various countries, such as BA.4.6, BF.7, BA.5.2.6, BA.4.1.9, and BE.1.2 harboring Arg346Thr; BA.4.7 and BF.13 harboring Arg346Ser; and BA.5.9 with Arg346Ile mutations.
Already these subvariants, especially BA.4.6, exhibit growth advantages compared with other variants including the original BA.4 and BA.5 strains.
However, the spike 346 mutations are further helping these new subvariants in terms of humoral immunity evasion.
The study findings were published as a correspondence in the peer reviewed journal: The Lancet Infectious Diseases.
The study was led by a world prominent immunologist and biochemist, Professor Dr Yunlong Cao from the Biomedical Pioneering Innovation Center at Peking University.
Many other world-famous virologists and researchers have also been warning about these various new emerging Omicron variants and sub-lineages exhibiting the 346 spike mutations that are expected to play a key role in the Fall and Winter of 2022 COVID-19 surges globally.
Past studies had also identified Arg346 as an important immunogenic residue because Arg346 mutations would allow the virus to escape neutralization by a large variety of neutralizing antibodies.
According to the Chinese study team, unlike the Arg346Lys mutation carried by BA.1.1, which maintained a similar chemical property, mutations from Arg to either Thr, Ser, or Ile correspond to a much stronger shift in antibody recognition.
The Chinese researchers warn
the efficacy of vaccines and neutralizing antibody drugs against these BA.4 and BA.5 sub-lineages needs immediate detailed evaluation.
The study team measured the neutralizing titers of plasma samples against the SARS-CoV-2 BA.4 and BA.5 subvariants with Arg346 mutations.
All the plasma samples were obtained from vaccinated individuals that received three doses of an inactivated vaccine (CoronaVac) without SARS-CoV-2 infection or with BA.1, BA.2, or BA.5 breakthrough infection.
Also, plasma from breakthrough infections were obtained 3 to 5 weeks after a positive PCR test for SARS-CoV-2. Vesicular stomatitis virus-based pseudo viruses were used in the neutralization assays.
The study findings showed that plasma samples from individuals who received three doses of CoronaVac without infection showed a 1·5–1·7-fold decrease in 50% neutralization titers (NT50) against BA.4 or BA.5 sub-lineages with Arg346Ile (BA.5.9), Arg346Thr (BA.4.6), and Arg346Ser (BA.4.7), compared with the NT50 against BA.4 or BA.5.
Furthermore, a similar reduction in neutralization titers was also observed in plasma from BA.1 or BA.2 breakthrough infection convalescents.
Most importantly, the study findings showed that BA.4 or BA.5 sub-lineages with Arg346Ile, Arg346Thr, or Arg346Ser mutations could significantly evade neutralization by plasma samples from BA.5 breakthrough infection, exhibiting a 2·4–2·6-fold decrease in NT50.
However, in contrast, the antibody-escaping capability of BA.1.1 that harbors a Arg346Lys mutation is similar to BA.1, as expected.
The study findings indicate the strong humoral immunity evasion capability of BA.4 and BA.5 sub-lineages with Arg346 mutations, suggesting that these sub-lineages, including BA.4.6, BA.4.7, BA.5.9, BF.7, BA.5.2.6, BA.4.1.9, BE.1.2, and BF.13 might gain an advantage in transmissibility under the global background of the pandemic caused by BA.4 and BA.5 sub-lineages.
It should be noted however that the BA.5 convalescent plasma shows higher neutralization titers against BA.5 than BA.1 and BA.1.1, but due to immune imprinting, or so-called original antigenic sin, convalescent plasma from omicron (including BA.1, BA.2, and BA.5) breakthrough infection is more effective against the ancestral strain with Asp614Gly compared with the respective infected strain.
The study team also evaluated the pseudo-virus-neutralizing activities of the approved neutralizing antibody drugs, including 11 monoclonal antibodies and four cocktails, against the Arg346-mutated BA.4 and BA.5 sublineages.
It was worryingly found that Cilgavimab did not affect BA.4 and BA.5 sub-lineages with Arg346Ile, Arg346Thr, or Arg346Ser mutations, resulting in the complete loss of efficacy of Evusheld (tixagevimab with cilgavimab) against BA.4.6, BA.4.7, BA.5.2.6, and BA.5.9 sub-lineages.
It was also found that the neutralizing activity of REGEN-COV (casirivimab with imdevimab was also reduced due to decreased reactivity of imdevimab against Arg346-mutated sub-lineages.
Shockingly, the potency of sotrovimab was further reduced. Of note, bebtelovimab remained highly potent and was the only neutralizing antibody drug approved by the US Food and Drug Administration.
The researchers however told Thailand Medical News
, “It should be noted that other emerging spike mutations being found alongside the 346 mutations in some of these new emerging sub-lineages are also reducing the efficacy of bebtelovimab!”
The study findings suggest that significant humoral immune evasion, especially against convalescents from BA.4 and BA.5 breakthrough infection, contributes to the emergence and rapid spread of multiple Arg346-mutated BA.4 and BA.5 sub-lineages.
The study team warns that the decreased neutralization titers of plasma samples from BA.5 breakthrough-infection convalescents indicate worrisome potential reinfection of BA.4.6 after the recovery from BA.4 or BA.5 infection.
Alarmingly, individuals that received Evusheld as long-term prophylaxis, especially those that are immunodeficient or exhibit high-risk comorbidities, are at particular risk of those subvariants.
Furthermore, the current BA.4 and BA.5-based vaccine boosting strategies should be evaluated in light of the prevalence of these BA.4 and BA.5 subvariants.
The world is entering a fall and winter period for the Northern hemisphere that is going to be catastrophic as governments are simply ignoring all the warning signs and all safety precautions have been removed coupled with the fact that many are in denial or are simply stupid and have no clue what is approaching. We can definitely witness an unprecedented rise in hospitalizations and deaths this late fall and the whole of winter.
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