SARS-CoV-2 B.1.1.420 and B.1.617.1 immune escape variants reported in France

Since its emergence in Wuhan, China, in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 (coronavirus disease 2019), is rapidly spreading, with numerous variants being observed around the world. A high transmission rate would indicate an undergoing process of positive selection of variants, which might allow the virus to acquire some advantageous genetic traits. Emerging variants are likely to be more transmissible, more pathogenic, and more likely to escape natural immunity or vaccine immunity.

Therefore genomic surveillance of SARS-CoV-2 and its variants is essential. It provides insights into the mechanisms behind viral dissemination worldwide. The variants include N501Y, E484K, or L452R mutations on gene coding to the viral spike protein. The two new Indian variants recently identified are N440K and the E484Q and L452R mutations associated with impaired antibody response and immune reactions.

Researchers discovered the first N440K variant and the new E484Q and L452R Indian variants isolated in France in a recent study. They presented the genetic mutations in the isolated genomes and the phylogenetic tree, including these strains among different SARS-CoV-2 clades. This work is posted on the bioRxiv* preprint server.

"Real-time close monitoring variants could help the scientific community to prevent fast-spreading and raise alarms towards potentially harmful variants."

The two new variants with N440K and E484Q and L452R mutations are associated with impaired antibody response and immune reactions. These were first identified in India. Alphabio's medical laboratory in Marseille (France), in collaboration with the Agence Régionale de Santé PACA, Marseille, began a real-time genomic survey of the SARS-CoV-2 circulating variants based on high-throughput whole-genome sequencing from the first of March 2021.

The project aims to characterize specific clusters and identify new emerging variants responsible for increased infectivity and/or immune escape. In this study, the researchers described the characterization of the two immune escape variants for the first time.

They isolated the first N440K escape variant from a 36-year-old French woman and her 37-year-old husband on the 16th of March, 2021. Both had mild symptoms, including asthenia and cough, without comorbidity or severity factors and were recovering. They were not vaccinated against the COVID-19 virus, and they did not have any history of travel abroad.

The researchers isolated the second E484Q - L452R variant from a 37 –year-old Indian man from Mumbai, who arrived in Marseille to embark on a ship as a crew member. On the 19th of March, 2021, upon developing mild symptoms including asthenia (physical weakness and lack of energy) and cough without comorbidity or severity factors, he was tested positive for the first time for SARS-CoV-2. He was immediately isolated in quarantine in a city hotel.

Analysis of the whole genome sequencing revealed that these belonged to the lineages B.1.1.420 and B.1.617.1 - these strains belong to the Clade 20B and 20A, respectively and are distant from other variants of concern.

The researchers emphasize that accurate and timely detection of new variants that may show greater infectivity or worse clinical symptoms, including immune escape, will be extremely important to prevent a worsening of the pandemia.

"In this study, the discovery of the first N440K variation isolated in France within infected subjects presenting no history of recent travelling highlights the importance of monitoring the impact of new viral variants," the researchers pointed the significance.

Notoriously the N440K mutation has been reported in India to be resistant to class 3 monoclonal antibodies (mAbs) C135 and REGN10987, in addition to have an enhanced binding affinity to the ACE2 (angiotensin-converting enzyme) receptor in humans. It may also have the potential for a higher transmission rate.

While it is not known yet whether the mutation affects the replicative fitness of the virus, the researchers warn that as a new emerging variant, its low prevalence could also be explained by the lack of sequencing in the infected population carrying this mutation. Thus leading to an underestimation of the spread of this variant, they hypothesized that the emergence of the N440K variant is the result of an intrahost evolution.

The latter case of the identification of the B.1.617.1 genome with the combination of the two RBD mutations 135 E484Q or L452R noted in this study raises the question of the lack of real control over the mobility of people from areas where variants of concern are circulating.

"Considering the immune escape conferred by the N440K, E484Q and L452R mutation, these new variants must be further surveyed."

Despite vaccines and mitigation measures, the COVID-19 pandemic continues, with more variants and more infections daily. If it is a variant accelerating the spread of the virus in human populations, necessary action needs to be taken rapidly to mitigate the epidemic. More coronavirus genomes need to be sequenced across the globe to identify the emergence of these mutations and other variants accurately.

*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.

Journal reference:
Dr. Ramya Dwivedi

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.


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