To date, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected about 251 million individuals and claimed more than five million lives worldwide.

In March 2020, the World Health Organization announced this outbreak to be a pandemic, which is popularly known as the coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 was first reported in 2019 in Wuhan, China, and has been characterized as a positive sense ribonucleic acid (RNA) virus belonging to the family Coronaviridae.

Study: SARS-COV-2 Delta variant displays moderate resistance to neutralizing antibodies and spike protein properties of higher soluble ACE2 sensitivity, enhanced cleavage and fusogenic activity. Image Credit: Vitalij Terescusuk / Shutterstock.com

SARS-CoV-2 infection and evolution

SARS-CoV-2 consists of four structural proteins that include the spike (S), envelope (E), nucleocapsid (N), and membrane (M), and several accessory proteins. The receptor-binding domain (RBD) of S glycoprotein, which is present on the surface of SARS-CoV-2, binds the angiotensin-converting enzyme 2 (ACE2) receptor of the host cell to facilitate infection. This is the reason why the S protein has been the primary target of current therapeutic neutralizing antibodies (nAbs) and vaccines.

The continual evolution of SARS-CoV-2, owing to mutations, resulted in the emergence of several variants. These variants have been categorized as variants of concern (VOC) and variants of interest (VOI).

Scientists have stated that VOCs like the UK-B.1.1.7 (Alpha), South Africa-B.1.351 (Beta), and Delta (B.1.617.2) strains are more virulent and are associated with greater transmissibility than the original SARS-CoV-2 strain. Mutations in the RBD region of the S protein have increased affinity towards ACE2 and contributed to immune escape.

The emergence of SARS-CoV-2 variants has posed a threat to the efficacy of the COVID-19 vaccines, as all current COVID-19 vaccines have been developed against the S protein of the original SARS-CoV-2 strain. Previous studies have shown a significant reduction in the neutralization potency of convalescent and vaccine sera. Mutations owing to substitution and deletion at the S and N protein sites lead to enhancement in the ACE2 binding, which increases the rate of transmission and evades immune protection induced by either vaccination or natural infection.

At present, the SARS-CoV-2 Delta variant has been the dominant variant of B.1.617 lineage, which is constantly evolving. This demands continual characterization to evaluate the neutralization potency of convalescent and vaccine-elicited sera, as well as the potency of therapeutic neutralizing antibodies.

About the study

A new study published on the bioRxiv* preprint server has estimated the efficacy of the immune response induced by vaccination and natural COVID-19 infection, as well as therapeutic neutralizing antibodies against the Kappa (B.1.617.1) and Delta (B.1.617.2, AY.1) lineages.

During the second wave of the COVID-19 pandemic, the emergence of SARS-CoV-2 B.1.617 lineage variants include the Kappa (B.1.617.1), and Delta (B.1.617.2, AY) strains occurred. However, the Delta variant has become dominant worldwide and continues to mutate. Researchers of the current study also determined the influence of the RBD substitutions in conferring resistance.

In the current study, researchers investigated the cross-neutralization potency of sera from individuals in the United States who recovered from SARS-COV-2 infection against pseudoviruses bearing spikes of B.1.617.1 and B.1.617.2 variants and their corresponding RBD mutations. Pseudoviruses with the B.1.617.1, B.1.617.2, and AY.1 S protein revealed partial reduction (1.5 to 4.4-fold) in neutralization titer by convalescent sera and vaccine-elicited sera.

The current study evaluated 23 therapeutic neutralizing antibodies, among which the Kappa and Delta pseudoviruses showed complete resistance to five and partial resistance to one antibody. Researchers revealed that the two-doses of messenger ribonucleic acid (mRNA) vaccines will possibly induce protective immunity against the tested B.1.617 variants.

Additionally, 17 of the 23 tested therapeutic neutralizing antibodies were found to completely neutralize B.1.617 variants. However, five therapeutic neutralizing antibodies that showed resistance may be due to RBD substitutions like L452R, K417N, and E484Q, but not T478K.

The authors emphasized the importance of continuously monitoring B.1.617.2 variants to detect new substitutions in S protein. This is because mutations at S protein could hamper the efficacy of vaccines, as well as therapeutic neutralizing antibodies.

Importantly, this study demonstrated that P681R substitution confers enhanced furin processing in the S protein of B.1.617 lineage variants, which is correlated to increased cell-cell fusion activity. There researchers have also revealed that only the Delta S protein displayed greater sensitivity to soluble ACE2 inhibition, thereby suggesting enhanced ACE2 affinity. These two features of the Delta variant are the foremost reasons for its global dominance.

Conclusion

The current study has a few limitations that include a smaller number of sera samples of SARS-CoV-2 convalescent and vaccinated individuals. Furthermore, the neutralization titer is dependent on the COVID-19 severity of the individual and the time of sample collection.

The researchers also found that the resistance to immune responses induced by both vaccination and natural infection was mainly due to RBD substitutions E484Q, T478K, and L452R. Neutralization titers and antigenic maps exhibited a full set of RBD substitutions.

The scientists have also pointed out that the combination of RBD substitution with mutations outside the RBD contributes to antigenic differences among B.1.617.1, B.1.617.2, and C.37 variants. More studies are required to elucidate the differences between convalescent and vaccine-elicited immune responses that could be impacted by the recent global dominance of B.1.617.2 and its sublineages.

*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

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.