Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination

Abstract

Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines based on updated variants are likely to be required over time to prevent productive infection. This study also suggests that two dose regimes of vaccine are required for maximal BNT162b2 and ChAdOx1-induced immunity.

Fig 1. Emergence of B.1.617.2 in the UK.

(A). Weekly SARS-CoV-2 genome sequences of delta/B.1.617.2 (pink), alpha/B.1.1.7 (grey), and all other lineages (blue) in the UK, represented as a (stacked) percentage of all UK sequences that week, up to the week beginning 29^th May 2021. Heatmap visualisation of spike mutations within UK B.1.617.2 SARS-CoV-2 genome sequences (B). Columns represent different amino acid mutations within the spike protein, whilst rows represent different specific combinations of spike mutations (“backbones”). Only non-synonymous mutations (blue or pink for those with a known antigenic effect) and deletions (black) were considered, and only backbones observed 10 or more times are displayed. The observed frequency for each backbone is visualised in the Freq column whilst the antigenic column represents the total number of known antigenic mutations in the backbone; the backbone from the AY.1 lineage (derived from Nepal; containing mutations W258L and K417N) is also included (top row). The heatmap is hierarchically clustered based on the Euclidean distance between spike backbones (rows); backbones missing specific mutations/deletions could be indicative of Ns (failed amplicons) in the genome sequence at those sites rather than true absence.

Fig 2. Spike mutations within variants of concern.

(A) Non-synonymous mutations (pink) and deletions (black) are shown for the variants of concern: B.1.1.7, B.1.351, B.1.617.1 and B.1.617.2, and P.1. Purple is used to distinguish secondary non-synonymous mutations at the same position, for example E484K (pink) and E484Q (purple). The region of the spike protein the mutation is located is highlighted on the top row; N-terminal domain (NTD), NTD antigenic supersite (NTDSS), receptor binding domain (RBD), receptor binding motif (RBM), furin cleavage site, S1 (NTD, NTDSS, RBD, RBM and furin are also in S1) and S2 subunits. Spike protein structure showing key B.1.617.2 mutations (B). Surface representation of spike homotrimer in open conformation with one upright RBD overlaid with ribbon representation (RCSB Protein Data Bank ID 6ZGG [26], with different monomers shown in black, pale blue and gold. Residues involved in B.1.617.2 lineage defining substitutions or deletions are shown as red spheres on each of the three monomers and are labelled on the monomer with an upright RBD, shown in black. Scissors mark the approximate location of an exposed loop (residues 677–688), containing the furin cleavage site, and including residue 681, which is absent from the structure.

Fig 3. Antibody response elicited by SARS-CoV-2 vaccines.

Sera from participants in the DOVE study were analysed by ELISA or pseudotype-based neutralisation assay. (A, B) ELISA reactivity in sera from individuals vaccinated with one or two doses of either BNT162b2 (A) or ChAdOx1 (B) was measured against recombinant S1 and RBD. Each point represents A450nm, cut-offs for S1 and RBD respectively are denoted by dotted lines. (C-F) Neutralising antibodies from individuals vaccinated with one or two doses of BNT162b2 (C and D) or ChAdOx1 (E and F) were quantified against HIV(SARS-CoV-2) pseudotypes bearing the Wuhan-Hu-1, B.1.617.1, B.1.617.2 or B.1.351 spike glycoproteins. Each point is the mean of three replicates, violin plot illustrates median plus quartiles. Mean titres were compared by one-way ANOVA. (G-J) Neutralising antibody titres were categorised based into the four viral variants against which they were determined; Wuhan-Hu-1 (G), B.1.617.1 (H), B.1.617.2 (I) or B.1.351 (J). Samples were then subdivided into one or two doses of BNT162b2 or ChAdOx1 respectively for each variant and compared (one-way ANOVA, Tukey’s multiple comparison’s test). Vaccination with two doses of BNT162b2 induced significantly higher titres of antibody against the Wuhan-Hu-1 virus than either one dose of BNT162b2, or two doses of ChAdOx1 (**** p<0.0001, ** p = 0.0011).