Coronavirus News: Details Emerge Regarding Impact Of B117 Variant And Spike Mutations On Monoclonal Antibodies And Sera

Coronavirus News: Researchers from University College London-UK, University of Amsterdam-Netherlands, King's College London-UK, the Francis Crick Institute-UK and University of Cambridge-UK in a new study have demonstrated that the neutralizing activity of monoclonal antibodies can be dramatically reduced by mutations of the SARS-CoV-2 spike glycoproteins unlike polyclonal antibodies generated after natural infection that remain active regardless of any introduced amino acid changes. The B.1.1.7 that carries numerous spike mutations also demonstrated reducing neutralizing capabilities by a variety of monoclonal antibodies.


 
From the published study abstract, ”Multiple SARS-CoV-2 vaccines have shown protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, Spike. Antibodies from SARS-CoV-2  infection neutralize the virus by focused targeting of Spike and there is limited serum cross neutralization of the closely-related SARS-CoV. As new SARS-CoV-2 variants are rapidly emerging, exemplified by the B.1.1.7, 501Y.V2 and P.1 lineages, it is critical to understand if antibody responses induced by infection with the original SARS-CoV-2 virus or the current vaccines will remain effective against virus variants. In this study the study team evaluated the neutralization of a series of mutated Spike pseudotypes including a B.1.1.7 Spike pseudotype. The analyses of a panel of Spike-specific monoclonal antibodies revealed that the neutralizing activity of some antibodies was dramatically reduced by Spike mutations. In contrast, polyclonal antibodies in the serum of patients infected in early 2020 remained active against most mutated Spike pseudotypes. The majority of serum samples were equally able to neutralize the B.1.1.7 Spike pseudotype, however potency was reduced in a small number of samples (3 of 36) by 5–10- 33 fold. This work highlights that changes in the SARS-CoV-2 Spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their impact on vaccine efficacy.”
 
The study findings were published on a preprint server and have yet to be peer reviewed. https://www.biorxiv.org/content/10.1101/2021.01.15.426849v1
 
It must be noted that serum neutralization activity is considered the most important correlate of protection against viral infections after natural exposure to the virus or following vaccination. The same is valid for the SARS-CoV-2 coronavirus, a causative agent of the rampant coronavirus disease (COVID-19) pandemic.
 
Importantly efficacious protection is not reliant only on potency but also on an adequate breadth of serum neutralization due to high-level variation in major antigens of certain viruses. The classic example is the influenza virus, where the lack of breadth hampers the generated antibody response's protective capacity.
 
Hence as many novel SARS-CoV-2 variants are emerging rapidly worldwide (exemplified by the B.1.1.7, P.1, and 501Y.V2 lineages), it is pivotal to understand whether antibody responses induced by the infection with the virus or by currently available vaccines will also be effective against these new variants.
 
The study team led by Dr Chloe Rees-Spear fr om the University College London in the United Kingdom decided to appraise the neutralization of a series of mutated spike glycoprotein SARS-CoV-2 pseudotypes including the infamous B.1.1.7 variant.
 
The study team evaluated the purported role of individual amino acids in enabling the escape from neutralizing antibodies. Initially, a series of point mutations were made to modify the amino acids in SARS-CoV-2 to match those at analogous position in SARS-CoV (i.e., a causative agent of the original SARS outbreak in 2002/2003).
 
Subsequently the next step was to emulate individual point mutations that tend to emerge in the real world by generating a pseudotype virus with the use of the B.1.1.7 variant spike sequence. Viral pseudotype mutants were then screened with highly specific assays.
 
The key goal of the study was to assess the impact of SARS-CoV spike glycoprotein substitutions on SARS-CoV-2 monoclonal antibody neutralization, as well as to appraise the impact on serum neutralization. Semi-quantitative enzyme-linked immunosorbent assay (ELISA) was one of the main tools in this endeavor.
 
Alarmingly the study findings showed that the spike glycoprotein mutations can reduce or eliminate neutralizing activity by individual monoclonal antibodies; on the other hand, serum neutralization was not so strongly affected.
 
However only one engineered mutation and none of the perceived spike glycoprotein mutations of the B.1.1.7 variant resulted in an outright escape from neutralizing activity, which was observed for only one out of 36 included serum samples.
 
Corresponding author Dr McCoy LE from the Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London told Thailand Medical News, "Our results suggest that the majority of vaccine responses should be effective against the B.1.1.7 variant, as the sera evaluated were obtained after infection early in the pandemic when the commonly circulating virus was highly similar in sequence to the vaccines now being deployed.”
 
Importantly as well, diminished potency by 5-10 fold was seen in only a small number of samples (i.e., 3 out of 36) interrogated against B.1.1.7 strain; nonetheless, all neutralization titers were still above 1:200 in basically all the cases.
 
A possible explanation of why a greater effect is observed on monoclonal antibodies compared to sera is the intrinsic polyclonality specific for serum neutralization. In other words, when many antibodies target major neutralizing sites in slightly different ways, it is far less sensitive to spike glycoprotein mutations.
 
Dr McCoy LE  explained, "This work highlights that changes in the SARS-CoV-2 spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their impact on vaccine efficacy.”
 
An important finding from the study was that the strongest effect on serum samples from mild infection was mediated by the TEI470-2NVP substitution, which is part of what has been termed the RBD binding ridge, and other mutations in this region can decrease serum neutralization. https://www.biorxiv.org/content/10.1101/2020.12.31.425021v1.full
 
As such, any mutation in this zone should be closely monitored in viral populations due to the potential for escape.
 
Theoretically it is likely that combinations of mutations have more potential to lead to loss of serum activity than individual single amino acid changes by destroying multiple parts of key epitopes. This has partially been observed in terms of the new B.1.1.7 Spike pseudotype analyzed here. Only one mAb was more dramatically affected by the full set of B.1.1.7 363 mutations. However, the small number of serum samples with reduced neutralization relative to the D614G virus, were more strongly affected by B.1.1.7 than either the ΔH69/V70 or N501Y 365 mutations individually.
 
This reduced neutralization was seen in 11% (3–5-fold) and 366 8% (5–10-fold) when tested against the B.1.1.7 Spike pseudotype.
 
However, all of the affected samples were still able to neutralize B.1.1.7, and the average reduced serum ID50 value was 1:522. This is ten-times higher than the reported serum ID50 correlate of protection in animal studies and suggests these responses would likely still be effective against infection with B.1.1.7. The differences in the data observed with B.1.1.7 and the two individual mutations 372 ΔH69/V70 or N501Y highlight the importance of testing emerging variants in the full form.
 
Moreover, this approach may be important as combinations of mutations could enable individual antibody escape mutations that are disadvantageous for transmission to be propagated. For example, a residue such as S494 is involved both in ACE2 binding and mAb neutralization. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775788/
 
Hence, a mutation at S494 could decrease antibody function but also decrease host receptor recognition and limit infectivity. However, the detrimental effects of the mutation on infectivity could be compensated for if a S494 mutation occurred in concert with a mutation that strengthened a different part of the viral entry pathway as has been suggested in another study.https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v1
 
This highlights the need for rapid evaluation of variant strains upon emergence, potentially accelerated by computational modeling based on prior knowledge of the effects of individual changes.
 
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