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Correspondence
Neutralising antibody (median age 42 years [IQR 33–52]) after dropped below 40 on their later study activity against either one dose (n=149; median time visit about 3 months after their second after first dose=30 days [IQR 23–38]) or BNT162b2 dose. Published Online SARS-CoV-2 VOCs two doses (n=159; median time after To maximise population coverage, June 3, 2021 https://doi.org/10.1016/ second dose=28 days [IQR 21–37]) of the UK extended the interval B.1.617.2 and B.1.351 by S0140-6736(21)01290-3 BNT162b2 (Pfizer–BioNTech) against between the two BNT162b2 doses. BNT162b2 vaccination five SARS-CoV-2 strains: a strain with Although this might have had a the original spike sequence (Wild- limited impact of protection against The SARS-CoV-2 B.1.617.2 Variant type); a strain with an Asp614Gly parental SARS-CoV-2 strains or the of Concern (VOC), first detected in mutation isolated during the first B.1.1.7 variant, the potential impact India, is now dominant in the UK, wave of infection in the UK, in 2020 on protection from other VOCs is having rapidly1 displaced the B.1.1.7 (D614G); and VOCs B.1.617.2, B.1.351 poorly understood. We found that strain2 that emerged in the UK with (first detected in South Africa in late neutralisation of VOCs was markedly the second COVID-19 wave in late 2020), and B.1.1.7. different after only one dose of 2020. The efficacy of currently licensed Two doses of BNT162b2 elicited BNT162b2 (appendix p 2): although COVID-19 vaccines against B.1.617.2 ELISA-detected anti-Wild-type spike 177 (95%) of 186 participants tested is unknown; although it possesses antibodies in all participants, and NAb positive for anti-spike antibodies by 12 mutations in its spike protein activity against all strains, including the ELISA and mounted a detectable NAb relative to the wildtype SARS-CoV-2 three VOCs tested, in all except six (3%) response against Wild-type (median first detected in Wuhan, China, in and nine (5%) of 159 participants who IC50=68 [IQR 42–140]) and D614G
December, 2019, B.1.617.2 lacks lacked NAb activity against B.1.617.2 (median IC50=71 [IQR 46–111]), median mutations at amino acid positions 501 and B.1.351, respectively (appendix NAbTs against all VOCs were below or 484 in its ACE2 receptor-binding p 2). NAbTs of sera correlated well the quantitative limit of detection. domain, commonly associated with between Wild-type and variants Stratification of NAbTs into three
VOCs (appendix p 2) or escape from (appendix p 2; RS>0·82, p<2 × 10⁻¹⁶), groups (IC50 low [<40], medium See Online for appendix neutralising antibodies (NAbs). as well as between VOCs (B.1.617.2 [40–256], high [>256]) and assessment
To determine vaccine-induced NAb vs B.1.351: RS=0·85, p<2 × 10⁻¹⁶). of the significance of the shift in their escape by B.1.617.2 and compare However, NAbTs were 5·8-fold reduced distribution relative to Wild-type by activity to previous strains with against B.1.617.2 relative to Wild-type ordered logistical regression was more existing estimates for population- (95% CI 5·0–6·9), significantly more informative (appendix p 2). Whereas based vaccine efficacy, we carried reduced than against B.1.1.7 (2·6-fold only 39 (21%) of 186 samples had out an initial analysis of the Legacy vs Wild-type, 95% CI 2·2–3·1), and on a low NAbTs against Wild-type, this study, established in January, 2021, by similar order to the reduction observed proportion rose to 50% against B.1.1.7 University College London Hospital and against B.1.351 (4·9-fold vs Wild-type, (p=1·7 × 10⁻⁶) and further to 75% the Francis Crick Institute in London, 95% CI 4·2–5·7). against B.1.351 (p<3 × 10⁻¹⁶) and 68% UK, to track serological responses to Notably, across all variants, against B.1.617.2 (p<5 × 10⁻¹⁶). Notably, vaccination in prospectively recruited increased age significantly correlated the downwards shift in titres was also staff volunteers (appendix p 6). A with reduced NAbT (appendix p 2; significant when compared to B.1.1.7 detailed description of the methods, –0·33
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this VOC presents a dual challenge result of factors aside from virus strain CSw reports grants from BMS, of reduced vaccine efficacy akin (appendix p 5), providing a basis to Ono-Pharmaceuticals, Boehringer-Ingelheim, Roche-Ventana, Pfizer and Archer Dx, unrelated to to the B.1.351 VOC, and increased understand observed vaccine efficacy this Correspondence; personal fees from transmissibility beyond the B.1.1.7 failure in other combinations of vaccine Genentech, Sarah Canon Research Institute, VOC. The impact of such a change and target population.6 Medicxi, Bicycle Therapeutics, GRAIL, Amgen, AstraZeneca, BMS, Illumina, GlaxoSmithKline, MSD, is challenging to predict: it remains In the case of single-dose recipients, and Roche-Ventana, unrelated to this difficult to assess precisely to what our data show that NAbTs are Correspondence; and stock options from Apogen extent the reduction in NAbTs we significantly lower against B.1.617.2 Biotech, Epic Biosciences, GRAIL, and Achilles observe will impact vaccine efficacy and B.1.351 VOCs relative to B.1.1.7, Therapeutics, unrelated to this Correspondence. All other authors declare no competing interests. and increase disease severity in a implying that although a single dose ECW, MW, SG, and DLVB contributed equally. vaccinated population, especially given might still afford considerably more GKa, CSw, SGan, and DLVB are joint senior authors. the multiple factors that contribute protection than no vaccination, RB and DLVB are members of the Genotype-to- Phenotype UK National Virology Consortium. to this process, such as long-lived single-dose recipients are likely Funding details and acknowledgments can be humoral immunity.3 to be less protected against these found in the appendix. All data (anonymised) and Nevertheless, a recent analysis of SARS-CoV-2 variants. These data full R code to produce all figures and statistical analysis presented in this Correspondence are For data and R code see https:// available NAb and vaccine efficacy therefore suggest that the benefits available online on Github. github.com/davidlvb/Crick- data4 has attempted to establish of delaying the second dose, in terms Emma C Wall, Mary Wu, Ruth Harvey, UCLH-Legacy-VOCs-2021-05 correlates of protection against earlier of wider population coverage and Gavin Kelly, Scott Warchal, strains of SARS-CoV-2 and, in the increased individual NAbTs after the 7 Chelsea Sawyer, Rodney Daniels, context of this model, our data suggest second dose, must now be weighed Philip Hobson, Emine Hatipoglu, that most participants that received against decreased efficacy in the Yenting Ngai, Saira Hussain, two doses of BNT162b2 would be short-term, in the context of the Jerome Nicod, Robert Goldstone, protected against B.1.617.2 infection spread of B.1.617.2. Worldwide, our Karen Ambrose, Steve Hindmarsh, and associated disease—consistent data highlight the ongoing need to Rupert Beale, Andrew Riddell, with preliminary data5 inferring increase vaccine supply to allow all Steve Gamblin, Michael Howell, vaccine efficacy against B.1.617.2 in countries to extend second-dose George Kassiotis, Vincenzo Libri, the UK based on rates of S-gene target protection as quickly as possible. Bryan Williams, Charles Swanton, failure during quantitative RT-PCR In the longer term, we note that Sonia Gandhi, *David LV Bauer testing. With increasing case numbers both increased age and time since the [email protected] and the proportion of sequencing- second dose of BNT162b2 significantly Francis Crick Institute, London, UK (ECW, MW, RH, confirmed B.1.617.2 cases, coupled correlate with decreased NAb activity GKe, SW, CSa, RD, PH, SHu, JN, RG, KA, SHi, RB, AR, with wider availability of WHO against B.1.617.2 and B.1.351—both SGam, MH, GKa, CSw, SGan, DLVB); National Institute for Health Research (NIHR) University International Standards and Reference of which are also characteristic of College London Hospitals (UCLH) Biomedical Panels to standardise NAbTs across the population in the UK at highest Research Centre, London, UK (ECW, RB, VL, BW); laboratories, we expect that improved risk of severe COVID-19 (ie, older NIHR UCLH Clinical Research Facility, London, UK (ECW, RB, VL, BW); University College London, vaccine efficacy estimates will allow and vaccinated earlier), independent London, UK (EH, YN, VL, BW, CSw, SGan); more precise modelling of correlates of other existing factors such as Department of Infectious Disease, St Mary’s of protection in the coming months. compromised immune status or Hospital, Imperial College London, London, UK (GKa) However, it is worth highlighting that comorbidity, or geographic-specific 1 Public Health England. SARS-CoV-2 variants of in the case of two BNT162b2 doses, our responses to vaccination. concern and variants under investigation in cohort of generally healthy, relatively Consequently, further booster England, Technical briefing 13. May 27, 2021. young, recently vaccinated, and mostly immunisations of JCVI Priority Groups https://assets.publishing.service.gov.uk/ government/uploads/system/uploads/ single-ethnicity individuals presents a in the UK and similar groups in other attachment_data/file/990177/Variants_of_ reasonable best-case scenario for NAb counties, as well as others with Concern_VOC_Technical_Briefing_13_ England.pdf (accessed June 2, 2021). activity against SARS-CoV-2 variants. lower vaccine-induced NAbTs than 2 Rambaut A, Loman N, Pybus O, et al. Preliminary Indeed, regardless of the absolute the cohort of BNT162b2 recipients genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel vaccine efficacy requirements, peak studied here (ideally with modified set of spike mutations. Feb 4, 2021. NAbTs are significantly reduced against vaccines that induce NAbs that https://virological.org/t/preliminary-genomic- VOCs B.1.617.2 and B.1.351 compared broadly neutralise emerging VOCs) characterisation-of-an-emergent-sars-cov-2- lineage-in-the-uk-defined-by-a-novel-set-of- with NAbTs against earlier variants, are more likely to be required to spike-mutations/563 (accessed June 2, 2021). and consequently, vaccine efficacy maintain the highest levels of NAbs 3 Turner JS, Kim W, Kalaidina E, et al. SARS-CoV-2 infection induces long-lived bone marrow on an individual or sub-population in regions where B.1.617.2 or other plasma cells in humans. Nature 2021; published level will become more sensitive to equally NAb-resistant strains become online May 24. https://doi.org/10.1038/ reductions in NAbTs occurring as a prevalent. s41586-021-03647-4.
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4 Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med 2021; published online May 17. https://doi. org/10.1038/s41591-021-01377-8. 5 Bernal JL, Andrews N, Gower C, et al. Effectiveness of COVID-19 vaccines against the B.1.617.2 variant. KHub 2021; published online May 24. https://doi.org/10.1101/2021. 05.22.21257658 (preprint). 6 Madhi SA, Baillie V, Cutland CL, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Engl J Med 2021; 384: 1885–98. 7 Parry H, Bruton R, Stephens C, et al. Extended interval BNT162b2 vaccination enhances peak antibody generation in older people. MedRxiv 2021; published online May 17. https://doi. org/10.1101/2021.05.15.21257017 (preprint).
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