Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern
following vaccination
Authors: Chris Davis
1
, Nicola Logan
1
, Grace Tyson
1
, Richard Orton
1
, William Harvey
1
, John
Haughney
2
, Jon Perkins
2
, The COVID-19 Genomics UK (COG-UK) Consortium#, Thomas P.
Peacock
3
, Wendy S. Barclay
3
, Peter Cherepanov
4
, Massimo Palmarini
1
, Pablo R. Murcia
1
, Arvind
H. Patel
1
, David L. Robertson
1
, Emma C. Thomson
1
*, Brian J. Willett
1
* on behalf of the COVID-19
DeplOyed VaccinE (DOVE) Cohort Study investigators.
1
MRC University of Glasgow Centre for Virus Research, University of Glasgow, UK, G61 1QH.
2
Clinical R&D, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK.
3
Department of Infectious Disease, Imperial College London, UK, W2 1PG.
4
The Francis Crick Institute, London, NW1 1AT, UK.
# A full list of authors and their affiliations appears at the end of the paper
Corresponding authors: Tel: +44 1413302928, email: emma.thomson@glasgow.ac.uk
Tel: +44 1413303274, email: brian.willett@glasgow.ac.uk
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
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.
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Introduction
The B.1.617.2 (Delta) variant that spread from India in March 2021 is now the dominant SARS-
CoV-2 variant type in the United Kingdom
1
, replacing the B.1.1.7 (Alpha; “Kent”) variant and
spreading rapidly across the globe. The B.1.617.2 variant has been introduced into the UK on
multiple occasions, most commonly associated with international travel from India where it has
caused a large wave of COVID-19 infections and placed unprecedented demand on healthcare
services
2
. A key component of the UK response to COVID-19 is a campaign of mass vaccination,
prioritizing the population by age and other risk groups. Vaccination began in December 2020
using the BNT162b2 mRNA vaccine (PfizerBioNTech). The ChAdOx1 adenovirus vectored vaccine
(Oxford-AstraZeneca) was added from January 2021, with the mRNA-1273 vaccine (Moderna)
available from April 2020. Priority was given to administering the first dose of vaccine to as much
of the UK population as possible, with second doses given within 12 weeks, in line with the
guidance of the Joint Committee on Vaccination and Immunisation (JCVI). This delayed dosing
strategy is now being challenged by the emergence of the B.1.617.2 lineage of SARS-CoV-2.
Recent data from Public Health England suggest that following exposure to this lineage,
effectiveness of the BNT162b2 vaccine is reduced to 33.5% after one dose, and 87.9% following
two doses
3
. Further, the two-dose effectiveness of the ChAdOX1 vaccine is reduced to 59.8%
following exposure to B.1.617.2
3
.
The early virus sequences detected in India were reported to have two key amino acid
substitutions (L452R and E484Q) in the receptor-binding domain of the spike glycoprotein, the
main immunodominant region and the region involved in ACE2 binding. Accordingly, this resulted
in the widespread usage of the “double mutant” misnomer, and initial designation as the B.1.617
Pango lineage. Availability of further sequence data led to the assignment of sub-lineages:
B.1.617.1, B.1.617.2 and B.1.617.3, of which B.1.617.2 is now the dominant variant in the UK. The
three lineages are characterized by the spike mutation L452R, whilst E484Q is present in
B.1.617.1 and B.1.617.3 but not B.1.617.2. The substitution L452R has been shown previously to
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reduce binding by several monoclonal antibodies
4, 5, 6, 7, 8
and convalescent plasma
6
. Globally,
L452R has emerged independently in several lineages since November/December 2020
suggesting a role in immune-evasion and/or virus adaptation
9
. L452R is one of the defining
mutations of the lineage B.1.427/B.1.429, a variant of interest (VOI) first identified in California
and associated with reduced neutralisation titres with plasma from vaccinated or convalescent
individuals
7
. Investigation of the effect of RBD mutations on binding of convalescent plasma by
deep mutational scanning suggests the impact of E484Q is similar to that of E484K
10
, which has
been shown widely to diminish antibody binding, including those elicited by vaccination
8, 11
.
In this study, we investigated the neutralising capacity of sera from participants in the COVID-19
DeplOyed VaccinE (DOVE) Cohort Study who had been vaccinated with the BNT162b2 mRNA
vaccine (Pfizer-BioNTech ) or the ChAdOx1 adenovirus-vectored vaccine (Oxford-AstraZeneca) as
part of the national deployed vaccine strategy.
Results
Characterisation of B.1.617.2 spike sequences
The B.1.617.2 lineage has spread rapidly across the globe following detection in India in late 2020.
According to GISAID (https://www.gisaid.org - accessed on 10/06/2021), a total of 31,997
sequences (Europe = 24,606, Asia = 4,974, North America = 2,210, Oceania = 163, Africa = 36,
South America = 8) have been assigned to lineage B.1.617.2, predominantly from the UK (n =
22,619; reflecting the large-scale UK sequencing effort). The first B.1.617.2 sequence in the UK
occurred on the 18
th
March 2021 when the dominant UK lineage was B.1.1.7, and since the end
of May 2021, B.1.617.2 accounts for the majority of SARS-CoV-2 samples sequenced (Fig. 1A). In
order to make sure that our available reagents matched the majority of the circulating B.1.617.2
variants, we assessed the relative frequency of each spike mutation in all the available sequences
(Fig. 1B). Amino acid substitutions T19R, G142D, R158G, L452R, T478K, D614G, P681R, D950N
and deletion Δ156-157 were present in the majority of the B.1.617.2 variants as chosen in the
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spike constructs used in our assays described below. The B.1.617.2 lineage continues to evolve,
acquiring new mutations of concern such as K417N in the sub-lineage AY.1/B.1.617.2.1 (Fig. 1B).
Although each Pango lineage has a distinct mutation set, there are several similarities between
the spike mutational profiles of the VOCs B.1.351, B.1.1.7 and B.1.617.2 (Fig. 2). They each have
a deletion within the N-terminal domain supersite (NTDSS), at least one mutation in the receptor
binding motif (RBM), and B.1.1.7 and B.1.617.2 each have a mutation at P681 within the furin
cleavage site.
Antibody response post-vaccination
Sera were collected from 156 healthy individuals who had received one dose (n = 37) or two
doses (n = 50) of BNT162b2 (Pfizer-BioNTech), or one dose (n= 50) or two doses (n = 18) of
ChAdOx1 (Oxford/AstraZeneca) vaccines. Samples were screened initially by ELISA for reactivity
with recombinant S1, RBD and N from the Wuhan-Hu-1 SARS-CoV-2 sequence. Of those
individuals vaccinated with BNT162b2, only one individual given a single dose (1/37) failed to
mount a detectable antibody response against S1, all other samples were positive for reactivity
against both S1 and RBD (Fig. 3A). In contrast, four individuals given a single dose (4/50) of
ChAdOx1 failed to react with S1, although two of these samples bound the RBD antigen (Fig.3B).
All samples from individuals immunised with two doses of either BNT162b2 or ChAdOx1 reacted
strongly against both S1 and RBD. Antibody reactivity (A405nm) was significantly higher following
the second dose of either BNT162b2 (S1 and RBD, p<0.0001) or ChAdOx1 (S1 p=0.0006; RBD
p=0.0014) compared with a single dose of the respective vaccines. Moreover, reactivity against
S1 was significantly greater in the groups immunised with either one (p=0.0152) or two
(p=0.0145) doses of BNT162b2 in comparison with the groups immunised with one or two doses
of ChAdOx1 respectively. Similarly, reactivity against RBD was higher in samples from the groups
immunised with either one (p=0.0029) or two (p=0.0018) doses of BNT162b2 in comparison with
one or two doses of ChAdOx1 respectively. Eight individuals were identified with reactivity
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