A preliminary study has possibly determined why the SARS-CoV-2 Delta variant is more infectious and pathogenic than its ancestor.
Through a series of in vitro experiments, researchers have discovered that variant’s enhanced ability to induce cell-to-cell fusion (syncytia) and reduced susceptibility to vaccine and infection-induced antibodies together help make the Delta variant more infectious than previously circulating variants. The study, which is yet to be peer reviewed, is currently available on the bioRxiv preprint server.
The SARS-CoV-2 virus has undergone more than 12 000 mutations since it was first detected in December 2019, most of which are neutral and do not contribute to viral evolution. However, the acquisition of specific mutations in structural and non-structural proteins has caused the emergence of novel, more virulent SARS-CoV-2 variants.
Spike protein mutations are particularly concerning as they can significantly influence viral infectivity, virulence, and immune evasion ability.
The B.1.617 lineage drove a massive surge in new COVID cases in India. This lineage is further divided into three sub-lineages, namely B.1.617.1, B.1.617.2, and B.1.617.3. Although these emerged first in India, the B.1.617.2 or Delta variant or soon became dominant in many countries, including South Africa where it has driven a new surge of infections, particularly in Gauteng Province. The World Health Organization (WHO) has designated the Delta variant as a ‘Variant of Concern’ (VOC) due to its significantly increased infectivity and pathogenicity.
In the current study, the scientists have evaluated the susceptibility of the Delta variant to neutralisation by vaccine or natural infection-induced antibodies.
Delta variant mutations
The Delta variant’s spike protein contains nine mutations in the S1 subunit and one mutation in the S2 subunit. In the S1 subunit, five mutations are present in the N-terminal domain containing binding sites (epitopes) for neutralising antibodies. In addition, two mutations are present in the receptor-binding domain of the S1 subunit, which is known to influence antibody-mediated neutralisation and infectivity. Among the three remaining mutations, two are known to increase angiotensin-converting enzyme 2 (ACE2) binding, viral replication, and spike protein cleavage at the S1/S2 site.
Delta variant host cell entry
Using African green monkey and human cells, the researchers found that Delta can enter kidney cells of both species with similar efficacy as the wild-type SARS-CoV-2. However, for human colon and lung cells, Delta showed 1.5-fold and 2-fold higher invading ability, respectively, compared to the wild-type virus. Since the Delta variant spike protein did not exhibit increased ACE2 binding, the scientists suggest that increased entry of B.1.617.2 into colon and lung cells is not mediated by enhanced ACE2 binding.
Besides inducing fusion between the viral envelope and host cell membrane, the spike protein triggers the fusion of infected cells with nearby cells to form large multinucleated cells, known as syncytia. Given the fact that spike-induced syncytia formation contributes to COVID pathogenesis, the scientists investigated whether Delta variant infection is associated with increased syncytia formation.
By conducting in vitro experiments on human lung cells expressing high levels of ACE2, they found that Delta spike expression leads to 2.5-fold higher and larger syncytia formation than the wild-type spike expression.
Delta variant’s immune evasion ability less than Beta?
The scientists tested the ability of four therapeutic monoclonal antibodies to neutralise the Delta variant, of which only Bamlanivimab failed. The other three antibodies exhibited similar efficacy in neutralising both wild-type virus and Delta variant.
Antibodies derived from COVID recovered patients, and BNT162b2-vaccinated individuals showed only slightly reduced efficacy in neutralising the Delta variant as compared to the wild-type virus. In contrast, the B.1.315 or Beta variant, first detected in South Africa, showed a significantly higher ability to evade infection- and vaccination-induced immunity.
In summary
The study showed that Delta’s increased ability to invade lung cells may enhance infectivity and pathogenicity. Though it has lower susceptibility to antibody-mediated neutralisation, it is possible that Delta may be effectively controlled by immunity developed in response to natural infection or vaccination.
Source: News-Medical.Net
Journal information: Arora P. 2021. Increased lung cell entry of B.1.617.2 and evasion of antibodies induced by infection and BNT162b2 vaccination. bioRxiv. https://www.biorxiv.org/content/10.1101/2021.06.23.449568v1
