BREAKING! Scientists Warn That Imprinted SARS-CoV-2 Humoral Immunity Is Inducing Convergent Omicron RBD Evolution At An Unprecedented Rate!
Researchers from Peking University, Beijing - China and the Changping Laboratory, Beijing- China are warning that imprinted SARS-CoV-2 humoral immunity is inducing convergent Omicron RBD evolution.
Thailand Medical News
would like to add that in November 2020, when we covered a Harvard study and warned that the adoption and extensive usage of monoclonal antibodies and vaccines would lead to more mutations and the emergence of more immune evasive SARS-CoV-2 variants based on what has been observed in the earlier SARS-CoV virus and the nature of coronaviruses, we were ridiculed and many other garbage researchers came up with published garbage claiming that the vaccines and monoclonal antibodies do not drive SARS-CoV-2 mutations.
Fast forward, today we are in a situation where the SARS-CoV-2 virus is spawning thousands of new immune evasive variants and sub-lineages over the last six months and of these about 400 such variants and sub-lineages that have acquired the necessary viral fitness and are circulating around globally and silently wreaking havoc.
Although most of these new variants and sub-lineages are not causing disease severity and increased mortality yet except for those in the vulnerable groups(ie the aged, young ,obese, immunocompromised, those with existing comorbidities especially high blood pressure, diabetes, kidney disease and heart disease), they are causing breakthrough infections and reinfections and also co-infections and long COVID issues and are contributing to rising excess deaths especially from sudden heart failures and strokes.
The continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA. 5. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such convergent evolution and its impact on humoral immunity remain unclear.
The Chinese study team demonstrate that these convergent mutations can cause striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability.
The new BQ.1.1.10, BA.4.6.3, XBB, and CH. 1.1 variants are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level.
In order to delineate the origin of the convergent evolution, the study team determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents.
Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions in the epitope diversity of NAbs and increased proportion o
f non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted convergent evolution.
The study team also showed that the convergent RBD mutations could be accurately inferred by integrated deep mutational scanning (DMS) profiles, and the evolution trends of BA.2.75/BA.5 subvariants could be well-simulated through constructed convergent pseudovirus mutants.
The study findings suggest current herd immunity and BA.5 vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be highly prioritized, and the constructed mutants could help to examine their effectiveness in advance.
The study findings were published on a preprint server and are currently being peer reviewed.
This is one of the first few studies to examine how imprinted severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) humoral immunity drives convergent evolution in continuously emerging Omicron subvariants.
The study team however only investigated the humoral immune imprinting response only in recipients of inactivated vaccines, although messenger ribonucleic acid (mRNA) technology-based vaccines induce a stronger overall humoral immune response.
At present, the SARS-CoV-2 Omicron variant is rapidly and continuously evolving, leading to the simultaneous emergence of numerous subvariants.
However, despite divergent evolutionary courses of Omicron subvariants, mutations on the receptor-binding domain (RBD) region of their spike (S) protein converge on several hotspots such as R346, G446, N450, K356, K444, V445, L452, N460, F486, F490, R493, and S494.
Importantly, deep mutational scanning (DMS) has revealed most of the mutations on these residues are antibody-evasive.
Hence these new mutations adversely impact the efficacy of coronavirus disease 2019 (COVID-19) vaccines and antibody therapeutics.
To date, studies have barely investigated the driving force and need for these convergent mutations in Omicron subvariants, and how they impact humoral immunity also remains unclear.
The study team constructed pseudoviruses of 50 Omicron subvariants, including Omicron BA.2, BA.2.75, and BA.4/5, carrying convergent mutations.
The researchers examined the neutralizing activities of therapeutic neutralizing antibodies (NAbs) and convalescent plasma against them. The latter had monoclonal antibodies (mAbs) generated naturally following BA.2 and BA.5 breakthrough infections.
The study team then integrated DMS-derived data profiles of the new mAbs isolated from BA.2 and BA.5 convalescents, followed by t-distributed stochastic neighbor embedding (t-SNE) for visualization.
Subsequently, the study team determined the epitope groups of new mAbs.
The study team recruited cohorts of individuals who received three doses of CoronaVac with or without BA.1, BA.2 or BA.5 breakthrough infection. Then, they collected convalescent plasma samples on average around four weeks after hospital discharge. Likewise, they collected plasma from the CoronaVac vaccinees four weeks following the third vaccination.
The study team next examined the relative human angiotensin-converting enzyme 2 (hACE2) binding capability of these convergent variants by evaluating hACE2 inhibitory efficiency against the pseudoviruses. Notably, ACE2-binding affinity determines the transmission potential of a SARS-CoV-2 variant.
The research findings demonstrated that multiple Omicron convergent mutants could cause striking evasion of NAb drugs and convalescent plasma, including BA.5 breakthrough infection, while retaining adequate hACE2 binding capability.
Interestingly, among all tested variants, BQ.1.1.10, BA.4.6.3, XBB, and CH.1.1 emerged as the most antibody-evasive strains displaying even lower 50% neutralization titer (NT50) than SARS-CoV-1, suggesting high antigenic drift and potential serotype conversion.
The SA55 antibody was the only NAb demonstrating high neutralizing potency against all tested Omicron subvariants.
Importantly, among the tested variants, XBB and BQ.1.1 exhibited the strongest resistance to therapeutic mAbs and cocktails.
Plasma from convalescents with BA.5 breakthrough infection exhibited higher neutralization against BA.5 subvariants, such as BQ.1 and BQ.1.1. Clearly, Omicron BA.5-based vaccine boosters could prove beneficial against convergent variants of BA.5 sublineages. However, it is also likely that some mutations in the N-terminal domain (NTD), such as Y144del in BQ.1.18, could severely reduce BA.5 breakthrough infection plasma neutralization titers.
Alarmingly, the study findings suggest that the current herd immunity and vaccine boosters based on the Omicron BA.5 subvariant might not provide good protection against breakthrough infections by other Omicron subvariants.
The study team could identify only two major peaks, R346T/S and K444E/Q/N/T/M, representing immune pressure for BA.5-elicited antibodies. Intriguingly, these two mutational hotspots are the most frequently mutated in evolving Omicron BA.4/5 subvariants and occurred in multiple convergent sub-lineages.
Significantly, due to humoral immune imprinting elicited by vaccination or prior infection, Omicron breakthrough infection(s) caused significant reductions in the NAbs epitope diversity and a higher percentage of non-neutralizing mAbs, which, in turn, drove further convergent evolution.
It was also noted that nAb repertoires induced by all Omicron breakthrough infections were distinct from those stimulated by wild-type SARS-CoV-2 strains. Moreover, integrated DMS profiles pointed at convergent RBD mutations accurately. Similarly, the BA.2.75/BA.5 subvariants evolution trends could be simulated via study-constructed convergent pseudovirus mutants.
As there is an urgent need for broad-spectrum SARS-CoV-2 vaccines and new NAb drugs to combat emerging variants, these convergent mutants could help examine their efficacy.
The study team says that most importantly, these mutants could be safely constructed and experimented with in biosafety level 2 laboratories without giving rise to any infectious pandemic virus. For example, the study prediction model generated BQ.1.1 and CH.1.1 were highly similar to BA.5-S3 and BA.2.75-S4/S6, respectively.
Thailand Medical News
however disagrees with the further ‘pumping’ of resources and monies into new vaccines and antibody-based therapeutics but rather a concerted focus into developing cocktails of antiviral drugs to combat the SARS-CoV-2 virus.
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