High individual heterogeneity of neutralizing activities against the original strain and 9 different variants of SARS-CoV-2

Abstract

Since the beginning of the COVID-19 pandemic, several SARS-CoV-2 variants have sequentially emerged. In France, most cases were due to spike D641G-harbouring viruses that descended initially from the Wuhan strain, then by variant of B.1.160 lineage we called Marseille-4 since the summer of 2020, which was followed by the alpha (UK) and beta (South African) variants in early 2021. We determined the neutralizing antibody (nAb) titres in sera from convalescent individuals previously infected by these 4 major local variants and from vaccine recipients to the original Wuhan strain and 9 variants, including two recent circulating delta (Indian) isolates. The results show high interindividual heterogeneity in nAbs, especially according to the variant tested. Unexpectedly, the major variations among nAbs are based on the genotype responsible for the infection. Patients previously infected with the beta and B.1.160 variants had the lowest nAb titres. The highest titres were observed in patients vaccinated with the Pfizer/BioNTech COVID-19 vaccine, even with antibodies against the delta variant.

Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

“…However, our results suggest that reduced NAb binding to the NTD is one potential mechanism that deserves further investigation. The G142D mutation is located in close proximity to the alterations of E156G and DEL157-158 reported in all Delta VOC that is part of the N3 loop of the NTD 'super site' epitope recognized by NTD-directed NAbs and associated with reduced viral neutralization (28)(29)(30)(31)(32). Despite the well-known challenges of in-silico protein structure e prediction on the spike protein (e.g., preand post-fusion conformation, the impact of D614G and P681R mutations on furin cleavage structure, and native spike conformation vs various mutated spike protein and their effect on antibody binding to different NTD or RBD epitopes) all of our structural predictions modelled against different templates (native, NTD-or RBD antibody-bound) consistently predicted that G142D and T95I mutations contribute to significant changes in the NTD secondary structure, including the potential conversion of β -strand to α -helix around aa159-167 and 183-190 regions, hydrogen-bond changes due to altered residue charge at G142D, an enlarged pocket at T95I, and overall three dimensional NTD surface topography that is unfavorable to NAb binding in the presence of other Delta VOC signature mutations.…”