SARS-CoV-2 Omicron spike mediated immune escape, infectivity and cell-cell fusion (preprint)

The Omicron variant emerged in southern Africa in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that the Omicron spike confers very significant evasion of vaccine elicited neutralising antibodies that is more pronounced for ChAdOx-1 adenovirus vectored vaccine versus BNT162b2 mRNA vaccine. Indeed neutralisation of Omicron was not detectable for the majority of individuals who had received two doses of ChAdOx-1. Third dose mRNA vaccination rescues neutralisation in the short term. Despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is lower than for wild type Wuhan-1 D614G and Delta. We demonstrate significantly lower infectivity of lung organoids and Calu-3 lung cells expressing endogenous levels of ACE2 and TMPRSS2 but similar infection as compared to Delta when using H1299 lung epithelial cells. Importantly, fusogenicity of the Omicron spike is impaired, leading to marked reduction in syncitia formation. These observations indicate that Omicron has gained immune evasion properties whilst possibly modulating properties associated with replication and pathogenicity.

Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India (preprint)

In April 2021, after successfully enduring three waves of the SARS-CoV2 pandemic in 2020, and having reached population seropositivity of about 50%, Delhi, the national capital of India was overwhelmed by the fourth wave. Here, we trace viral, host, and social factors contributing to the scale and exponent of the fourth wave, when compared to preceding waves, in an epidemiological context. Genomic surveillance data from Delhi and surrounding states shows an early phase of the upsurge driven by the entry of the more transmissible B.1.1.7 variant of concern (VOC) into the region in January, with at least one B.1.1.7 super spreader event in February 2021, relatable to known mass gatherings over this period. This was followed by seeding of the B.1.617 VOC, which too is highly transmissible, with rapid expansion of B.1.617.2 sub-lineage outpacing all other lineages. This unprecedented growth of cases occurred in the background of high seropositivity, but with low median neutralizing antibody levels, in a serially sampled cohort. Vaccination breakthrough cases over this period were noted, disproportionately related to VOC in sequenced cases, but usually mild. We find that this surge of SARS-CoV2 infections in Delhi is best explained by the introduction of a new highly transmissible VOC, B.1.617.2, with likely immune-evasion properties; insufficient neutralizing immunity, despite high seropositivity; and social behavior that promoted transmission.

A rigorous framework for detecting SARS-CoV-2 spike protein mutational ensemble from genomic and structural features (preprint)

The recent release of SARS-CoV-2 genomic data from several countries has provided clues into the potential antigenic drift of the coronavirus population. In particular, the genomic instability observed in the spike protein necessitates immediate action and further exploration in the context of viral-host interactions. Here we dynamically track 3,11,795 genome sequences of spike protein, which comprises 2,584 protein mutations. We reveal mutational genomic ensemble at different timing and geographies, that evolves on four distinct residues. In addition to the well-established N501 mutational cluster, we detect the presence of three novel clusters, namely A222, N439, and S477. The robust examination of structural features from 44 known cryo-EM structures showed that the virus is deploying many mutations within these clusters on structurally heterogeneous regions. One such dominant variant D614G was also simulated using molecular dynamics simulations and, as compared to wild-type, we found higher stability with human ACE2 receptor. There is also a significant overlap of mutational clusters on known epitopes, indicating putative interference with antibody binding. Thus, we propose that the resulting coaxility of mutational clusters is the most efficient feature of SARS-CoV-2 evolution and provides precise mutant combinations that can enable future vaccine re-positioning.

Intra-host variability in global SARS-CoV-2 genomes as signatures of RNA editing: implications in viral and host response outcomes (preprint)

Since its zoonotic transmission in the human host, the SARS-CoV-2 virus has infected millions and has diversified extensively. A hallmark feature of viral system survival is their continuous evolution and adaptation within the host. RNA editing via APOBEC and ADAR family of enzymes has been recently implicated as the major driver of intra-host variability of the SARS-CoV-2 genomes. Analysis of the intra-host single-nucleotide variations (iSNVs) in SARS-CoV-2 genomes at spatio-temporal scales can provide insights on the consequence of RNA editing on the establishment, spread and functional outcomes of the virus. In this study, using 1,347 transcriptomes of COVID-19 infected patients across various populations, we find variable prevalence of iSNVs with distinctly higher levels in Indian population. Our results also suggest that iSNVs can likely establish variants in a population. These iSNVs may also contribute to key structural and functional changes in the Spike protein that confer antibody resistance.

Intranasal administration of SARS-CoV-2 neutralizing human antibody prevents infection in mice (preprint)

Prevention of SARS-CoV-2 infection at the point of nasal entry is a novel strategy that has the potential to help contain the ongoing pandemic. Using our proprietary technologies, we have engineered a human antibody that recognizes SARS-CoV-2 S1 spike protein with an enhanced affinity for mucin to improve the antibodys retention in respiratory mucosa. The modified antibody, when administered into mouse nostrils, was shown to block infection in mice that were exposed to high titer SARS-CoV-2 pseudovirus 10 hours after the initial antibody treatment. Our data show that the protection against SARS-CoV-2 infection is effective in both nasal and lung areas 7 days after viral exposure. The modified antibody is stable in a nasal spray formulation and maintains its SARS-CoV-2 neutralizing activity. Nasal spray of the modified antibody can be developed as an affordable and effective prophylactic product to protect people from infection by exposure to SARS-CoV-2 virus in the air. One-sentence summaryA Fc-modified human antibody prevents SARS-CoV-2 viral infection via nasal administration

Integrated genomic view of SARS-CoV-2 in India (preprint)

India first detected SARS-CoV-2, causal agent of COVID-19 in late January-2020, imported from Wuhan, China. March-2020 onwards; importation of cases from rest of the countries followed by seeding of local transmission triggered further outbreaks in India. We used ARTIC protocol based tiling amplicon sequencing of SARS-CoV-2 (n=104) from different states of India using a combination of MinION and MinIT from Oxford Nanopore Technology to understand introduction and local transmission. The analyses revealed multiple introductions of SARS-CoV-2 from Europe and Asia following local transmission. The most prevalent genomes with patterns of variance (confined in a cluster) remain unclassified, here, proposed as A4-clade based on its divergence within A-cluster. The viral haplotypes may link their persistence to geo-climatic conditions and host response. Despite the effectiveness of non-therapeutic interventions in India, multipronged strategies including molecular surveillance based on real-time viral genomic data is of paramount importance for a timely management of the pandemic.