SARS-CoV-2 Mutations: Study Confirms That 501Y.V2 Variant In South Africa Escapes Antibody Neutralization And Vaccines Likely Ineffective
: While certain vaccine manufacturers are releasing studies by their own staff claiming that their vaccines will still likely to work on the various emerging SARS-CoV-2 variants and many so called ‘credible’ American media are also publishing articles promoting this misinformation, South African researchers in a news study have confirmed that the 501Y.V2 variant escapes antibody neutralization that vaccines are likely to be ineffective.
The SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein.
In the study, the researchers demonstrated that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and indicates reduced efficacy of current spike-based vaccines.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.01.18.427166v1
The study team in South Africa conducted the study showing that the novel 501Y.V2 variant of SARS-CoV-2 coronavirus that has emerged in the country is able to escape the neutralizing antibodies that are elicited by previously circulating strains of the virus.
The SARS-CoV-2 is the agent responsible for the coronavirus disease 2019 (COVID-19) pandemic that is currently sweeping the globe, devastating public health and the global economy.
The team found that the 501Y.V2 lineage also conferred complete escape from three classes of therapeutic monoclonal antibodies.
Dr Penny Moore from the National Health Laboratory Service (NHLS) in Johannesburg and colleagues warns the findings highlight the possibility of re-infection among people presumed to have acquired some degree of immunity due to previously having had SARS-CoV-2.
The study findings also have important implications regarding the effectiveness of certain vaccines and therapeutic strategies that are undergoing development.
Typically two immunodominant spike regions are usually targeted by neutralization.
However the novel 501Y.V2 lineage contains multiple mutations within two immunodominant regions of the viral spike protein ie the main structure SARS-CoV-2 uses to bind to and infect host cells.
Importantly one of these regions ie the receptor-binding domain (RBD) is the primary target of antibody neutralization during infection.
Dr Moore told Thailand Medical News, “Neutralizing antibodies are considered the primary correlate of protection against re-infection for most vaccines and are being actively pursued as therapeutics. The overwhelming majority of monoclonal neutralizing antibodies isolated thus far from infected individuals, immunoglobulin libraries, or immunized animal models, target this region.”
The next most imm
unodominant region is the N-terminal domain (NTD) of the spike protein.
Importantly this domain is also frequently targeted by neutralizing antibodies and several potent monoclonal antibodies that target this region are currently being considered for clinical development.
Alarmingly the 501Y.V2 lineage of SARS-CoV-2 that has recently emerged in South Africa contains nine mutations in the spike protein. One cluster is seen in the NTD and includes four substitutions and one deletion (L18F, D80A, D215G, Δ242-244, and R246I). Another cluster is found in the RBD and consists of three substitutions (K417N, E484K, and N501Y).
Dr Moore added, “Although the 501Y change has been associated with increased transmissibility, rather than immune pressure, the accumulation of mutations specifically within these two immunodominant regions of spike is highly suggestive of escape from neutralization. Indeed, mutations at 484 have been shown to reduce neutralization sensitivity.”
It should also be noted that mutations in the RBD and NTD of spike have also been described in a novel variant that has recently emerged in Brazil.
Also, variants in the UK and United States have also been described, suggesting that new SARS-CoV-2 variants are emerging globally.
The study team showed that spike mutations in the 501Y.V2 lineage exhibited complete neutralization escape from three classes of SARS-CoV-2-directed monoclonal antibodies. Also this variant showed substantial or complete escape from neutralizing antibodies in plasma taken from individuals who had recovered from COVID-19.
Most significantly, the team showed that the K417N mutation played a crucial role in the viral escape. This mutation effectively abrogated neutralization by a well-defined, multi-donor class of antibodies that make up some of the most common and potent neutralizing antibodies to SARS-CoV-2.
Dr Moore further added, “Crucially, it is from these same public antibody responses that many therapeutic strategies currently under development have been derived. The overwhelming majority of monoclonal antibodies already on the path to licensure target residues K417 or E484 and will therefore be ineffective against 501Y.V2.”
The study team also defined an important role for a small three-amino-acid deletion in a relatively large region in NTD that completely disrupted a dominant antibody response to a site called the N5-loop or “supersite loop.”
Dr Moore explained, “This deletion predominates among 501Y.V2 variants and occurs either alone or with an R246I substitution that has also been shown to abrogate neutralization by several NTD-directed neutralizing antibodies
The study team also points out that a next generation of potent neutralizing antibodies targeting this NTD N5-loop supersite has been suggested for clinical development, but these are unlikely to be effective against 501Y.V2.
The study team says the research findings suggest that while many people worldwide have already been infected with SARS-CoV-2 globally and are presumed to have accumulated some level of immunity, new variants such as 501Y.V2 pose a significant risk of re-infection.
Importantly the research findings also raise important questions about the effectiveness of current spike-based therapeutic strategies and vaccines.
Dr Moore commented, “Altogether, these data highlight the need for increased, ongoing surveillance and sequencing during the SARS-CoV-2 pandemic. The speed and scope of 501Y.V2 mediated immune escape from pre-existing neutralizing antibodies highlight the urgent requirement for rapidly adaptable vaccine design platforms, and the need to identify less mutable viral targets for incorporation into future immunogens.”
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