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Numerous variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the initial Wuhan-Hu-1 prototype. The new variants evade pre-existing immunity by prompting a different antibody response than the prior variants.

Acknowledgment of the specificity of antibody response (by prior exposure or vaccination) is crucial to circumvent SARS-CoV-2 infections.

A recent study posted on the bioRxiv* preprint server evaluated the specificity of antibody response elicited by the Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Findings

The spike (S) protein of the Delta variant of SARS-CoV-2 harbors numerous mutations compared to Wuhan-Hu-1 variant, two of which are in the spike receptor-binding domain (RBD). The beta variant of the SARS-CoV-2 also contains multiple mutations including at RBD. Both, Delta and Beta variants have mutations at the antigenic site with decreased neutralization sensitivity to the vaccine-generated antibodies or to those generated due to the early 2020 infection – with Beta showing more reduction in neutralization.

The neutralization potency of the plasma was reduced by at least 48 folds on removing the Delta RBD-binding antibodies. The Beta variant, Delta variant, and early 2020 variants primarily rendered a neutralizing antibody response against the RBD although non-RBD epitopes were also targeted, while the neutralizing antibody responses elicited by mRNA vaccines are hyper-focused on RBD.

Neutralizing antibody response elicited by two doses of BNT162b2 vaccine focused completely on the RBD. Higher neutralization titers were recorded with Delta variant infection (against both, effects of fluoxetine on the brain Delta and D614G spike proteins) compared to those after two doses of COVID-19 vaccine, along with primarily RBD-focused neutralization antibody response. Although Delta infection elicited a moderate non-RBD neutralizing antibody response against the D614G spike, neutralizing antibody response against Delta spike was completely directed towards the RBD.

It was found that a polyclonal antibody response was elicited by the Delta variant and primarily focused on class 1 and class 2 epitope of the Barnes classification scheme. A massive effect on antibody binding was found with mutations at sites 478 and 484-486. Binding was impacted in most cases with a mutation at site-472. Reduction in antibody binding was also noted with mutations at the site P384 and class 4 epitope.

Compared to the Wuhan-Hu-1 variant, mutations at the Delta-RBD were either at or proximal to class 1 and class 3 epitopes. Antibody binding post-Delta infection was strongly affected by mutations at the site K478.

Antibody response to early 2020, the Delta or Beta variants were affected by mutations at class 2 epitope and at site 484. Meanwhile, class 3 epitope mutations at site 443-452 rarely affected binding, post-Delta variant infection. On the other hand, class 1 mutation-affected Delta-elicited antibodies had a lower effect on the Beta-elicited antibodies.

Plasma infected with the early 2020 virus generated multiple antibody classes but was more inclined towards class 2 antibodies. Plasmas of Beta variant clustered between class 2 and 3 antibodies, whereas plasma of Delta variant clustered between class 1 and class 2 antibodies.

Class 1 and class 2 epitopes are the sites of interest of the Delta variant infected plasmas with mutations at 417 and 484-486 sites – which hugely affects antibody binding. Mutations at site K417 massively affected the antibody binding of Delta breakthrough plasma compared to primary Delta infection plasma, whereas mutations at site K478 had a comparatively subdued effect. The findings suggested that the antibody immunity of Delta breakthrough was between primary Delta-elicited immunity and early 2020-elicited immunity.

Potent neutralization of D614G spike was noticed by the plasma of Delta breakthrough and two doses of BNT162b2 vaccine, whereas a potent neutralization of the Delta spike was seen with primary Delta infection. Mutations at Delta+K417N led to a three-fold lesser neutralization for Delta breakthrough plasmas and two doses of BNT162b2 vaccine compared to the Delta spike. A two-fold lesser neutralization potency was observed with the primary Delta infection against Delta+K417N compared to the Delta spike. However, the K417N mutation at the D614G spike did not have any effect on the vaccine-elicited plasma or the early 2020-infected plasma.

E484K mutations largely affected antibody neutralization for the mRNA vaccine-elicited plasma and early 2020-elicited plasma in the D614G background. In a few cases, E484K reduced neutralization to a similar degree as found by removing all RBD-binding antibodies. An eight-fold neutralization effect was found with the Delta+E484K against primary Delta-induced antibodies. Whereas for Delta breakthrough infection-induced antibodies and mRNA-vaccine elicited antibodies, a three-fold neutralization was noted—which is similar to the Delta+K417 mutation.

Besides, some 484-binding antibody attachments were speculated to have been disrupted by L452R mutation.

Conclusions

The results suggested that the Delta infection generates a response that more closely resembles that of the early 2020 infection rather than the Beta infection. Additionally, the Delta infection response showed subtle differences from the Delta breakthrough responses.

The findings illustrated the dependency of antigenic response of SARS-CoV-2 mutations on prior exposure history which will aid in the development of broad-spectrum vaccines.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Nidhi Saha

I am a medical content writer and editor. My interests lie in public health awareness and medical communication. I have worked as a clinical dentist and as a consultant research writer in an Indian medical publishing house. It is my constant endeavor is to update knowledge on newer treatment modalities relating to various medical fields. I have also aided in proofreading and publication of manuscripts in accredited medical journals. I like to sketch, read and listen to music in my leisure time.