Two separate studies in India and Japan on the Delta variant point to a key mutation and a possible combination with another as important factors behind its fitness advantage and ability to cause severe disease.
Though early studies had already indicated that the Delta variant is able to significantly escape vaccination-induced immune response and transmit faster than most known Variants of Concern (VoC), there was not much clarity about its virological properties. The new studies have attempted to answer that question and the answers appear to lie between mutations P681R and T478K, as per assessments so far. Three distinct subtypes of the B.1.617 have been identified so far — the B.1.617.1, the B.1.617.2 or Delta, and the B.1.617.3.
All three have the P681R mutation, which is said to drive syncytium formation – fusing of infected lung cells – associated with severe forms of SARS-COV-2, or Covid-19. The L452R, E484Q and D614G are other notable mutations in the B.1.617 lineage.
However, Delta has dropped E484Q and included the T478K mutation, which is also seen in Mexican variants and is under close watch for its role.
A pre-print research paper from Japan, however, terms the P681R mutation a ‘hallmark of the Delta variant’ that ‘facilitates the spike protein cleavage and enhances viral fusogenicity’ and shows ‘higher pathogenicity than the parental virus’. The study – SARS-CoV-2 spike P681R mutation, a hallmark of the Delta variant, enhances 2 viral fusogenicity and pathogenicity – was conducted by researchers from leading institutions that are part of the Genotype to Phenotype Japan (G2P-Japan) Consortium.
The study paper finds that the P681R caused formation of larger syncytia (fusion of infected cells in lungs) than other variants and effected higher pathogenicity even at a lower viral load, bringing about higher weight loss in infected hamsters as seen in experiments.
“Our data suggest that the higher Covid-19 severity and unusual symptoms caused by the B.1.617.2/Delta variant are partly due to the higher fusogenicity caused by the P681R mutation. Switching viral infection mode by the P681R mutation may relate to the severity and/or unusual outcome of viral infection,” it says.
Alongside is a detailed report from top Indian institutes on mutations that circulated in Maharashtra and drove the second wave. This study – published in Microorganisms, a scientific, peer-reviewed, open access microbiology journal – points to the combination of mutations that strengthened Delta’s unrelenting spread across the country.Authored by Dr Sujeet Singh, Director, National Center for Disease Control; Dr Priya Abraham of the National Institute of Virology and Dr Samiran Panda of the Indian Council of Medical Research, the article on — SARS-CoV-2 Spike Mutations, L452R, T478K, E484Q and P681R, in the Second Wave of Covid-19 in Maharashtra — details their respective roles.“The structural analysis of RBD mutations L452R, T478K and E484Q revealed that these may possibly result in increased ACE2 binding, while P681R in the furin cleavage site could increase the rate of S1-S2 cleavage, resulting in better transmissibility,” it says. The P681R mutation helped in an increased rate of membrane fusion, internalization and thus better transmissibility, it says.The T478K – also seen in Mexican variant B.1.1.222 — appears to work to Delta’s advantage via combination, it adds.