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BACKGROUND
The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear.

METHODS
We used a test-negative case–control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (S) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients’ vaccination status.

RESULTS
Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant.

CONCLUSIONS
Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations. (Funded by Public Health England.)

India has experienced a surge in cases of coronavirus disease 2019 (Covid-19) since late March 2021, reaching more than 400,000 cases and 4000 deaths reported each day in early May 2021.1 This increase has resulted in hospital services becoming overwhelmed and in a scarcity of oxygen supplies.2 Although only a small proportion of samples have been sequenced, B.1.617 lineages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have dominated. The B.1.617.2 (delta) variant was first detected in India in December 2020 and became the most commonly reported variant in the country starting in mid-April 2021.1 As of May 19, 2021, the variant had been detected in 43 countries across six continents in GISAID (originally an acronym for global initiative on sharing avian influenza data but more recently a site for compiling sequence data on viruses, particularly influenza and coronaviruses, that threaten to cause a pandemic).3 In the United Kingdom, a rapid increase in cases with this variant has been seen associated with travel from India and with community transmission.4

In the United Kingdom, vaccination was initially prioritized for older adults, caregivers, and health and social care workers, with subsequent rollout to persons in clinical risk groups and younger-age cohorts.5 At an early stage of the rollout, a policy decision, based on advice from the Joint Committee on Vaccination and Immunisation, was made to use an extended administration interval of up to 12 weeks in order to maximize the number of vulnerable persons receiving the first dose during the second wave of the pandemic in the context of constraints on vaccine supply and delivery.6

Vaccines have been found to be highly efficacious at preventing symptomatic disease, as shown by clinical trials7-9 and real-world evidence.10-14 The B.1.1.7 (alpha) variant, first identified in the United Kingdom, was the predominant lineage seen between January and May 2021. Levels of protection against the alpha variant that are conferred by vaccination are similar to those observed in clinical trials, with additional protection against severe disease.10,11,15-17 Laboratory data indicate that the B.1.351 (beta) variant has reduced neutralization, according to analysis of serum samples obtained from vaccinated persons.18,19 Observational data from Qatar indicated modestly reduced effectiveness against symptomatic disease caused by this variant but high levels of effectiveness against severe, critical, or fatal disease in persons vaccinated with the BNT162b2 vaccine (Pfizer–BioNTech).17 Furthermore, a trial of the NVX-CoV2373 vaccine (Novavax) showed 51.0% efficacy against the beta variant.20 Finally, high levels of neutralization have been seen with the P.1 (gamma) variant in serum samples obtained from persons vaccinated with the BNT162b2 vaccine, and one study showed only minimally reduced vaccine effectiveness against test-positive cases with one dose of messenger RNA vaccine.19,21,22

The delta variant is characterized by the spike protein mutations T19R, Δ157-158, L452R, T478K, D614G, P681R, and D950N.1 Several of these mutations may affect immune responses directed toward the key antigenic regions of receptor-binding protein (452 and 478) and deletion of part of the N-terminal domain.23 P681R is at the S1–S2 cleavage site, and it appears that strains with mutations at that site may have increased replication, which leads to higher viral loads and increased transmission.24 Data on the effectiveness of Covid-19 vaccines against clinical outcomes with this variant have been limited. In this study, we aimed to estimate the effectiveness of two Covid-19 vaccines, BNT162b2 and ChAdOx1 nCoV-19 (AstraZeneca), against symptomatic disease caused by the delta variant.

Methods
STUDY DESIGN
We used two approaches to estimate the effect of vaccination on the delta variant. First, we used a test-negative case–control design to estimate vaccine effectiveness against symptomatic disease caused by the delta variant, as compared with the alpha variant, over the period that the delta variant has been circulating. This approach has been described in detail elsewhere.10 In brief, we compared vaccination status in persons with symptomatic Covid-19 with vaccination status in persons who reported symptoms but had a negative test. This approach helps to control for biases related to health-seeking behavior, access to testing, and case ascertainment.

For the secondary analysis, the proportion of persons with cases caused by the delta variant relative to the main circulating virus (the alpha variant) was estimated according to vaccination status. The underlying assumption was that if the vaccine had some efficacy and was equally effective against each variant, a similar proportion of cases with either variant would be expected in unvaccinated persons and in vaccinated persons. Conversely, if the vaccine was less effective against the delta variant than against the alpha variant, then the delta variant would be expected to make up a higher proportion of cases occurring more than 3 weeks after vaccination than among unvaccinated persons. Details of this analysis are described in Section S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

DATA SOURCES
Vaccination Status
Data on all persons in England who have been vaccinated with Covid-19 vaccines are available in a national vaccination register (the National Immunisation Management System). Data regarding vaccinations that had occurred up to May 16, 2021, including the date of receipt of each dose of vaccine and the vaccine type, were extracted on May 17, 2021. Vaccination status was categorized as receipt of one dose of vaccine among persons who had symptom onset occurring 21 days or more after receipt of the first dose up to the day before the second dose was received, as receipt of the second dose among persons who had symptom onset occurring 14 days or more after receipt of the second dose, and as receipt of the first or second dose among persons with symptom onset occurring 21 days or more after the receipt of the first dose (including any period after the receipt of the second dose).

SARS-CoV-2 Testing
Polymerase-chain-reaction (PCR) testing for SARS-CoV-2 in the United Kingdom is undertaken by hospital and public health laboratories, as well as by community testing with the use of drive-through or at-home testing, which is available to anyone with symptoms consistent with Covid-19 (high temperature, new continuous cough, or loss or change in sense of smell or taste). Data on all positive PCR tests between October 26, 2020, and May 16, 2021, were extracted. Data on all recorded negative community tests among persons who reported symptoms were also extracted for the test-negative case–control analysis. Children younger than 16 years of age as of March 21, 2021, were excluded. Data were restricted to persons who had reported symptoms, and only persons who had undergone testing within 10 days after symptom onset were included, in order to account for reduced sensitivity of PCR testing beyond this period.25

Identification of Variant
Whole-genome sequencing was used to identify the delta and alpha variants. The proportion of all positive samples that were sequenced increased from approximately 10% in February 2021 to approximately 60% in May 2021.4 Sequencing is undertaken at a network of laboratories, including the Wellcome Sanger Institute, where a high proportion of samples has been tested, and whole-genome sequences are assigned to Public Health England definitions of variants on the basis of mutations.26

Spike gene target status on PCR was used as a second approach for identifying each variant. Laboratories used the TaqPath assay (Thermo Fisher Scientific) to test for three gene targets: spike (S), nucleocapsid (N), and open reading frame 1ab (ORF1ab). In December 2020, the alpha variant was noted to be associated with negative testing on the S target, so S target–negative status was subsequently used as a proxy for identification of the variant. The alpha variant accounts for between 98% and 100% of S target–negative results in England. Among sequenced samples that tested positive for the S target, the delta variant was in 72.2% of the samples in April 2021 and in 93.0% in May (as of May 12, 2021).4 For the test-negative case–control analysis, only samples that had been tested at laboratories with the use of the TaqPath assay were included.

Data Linkage
The three data sources described above were linked with the use of the National Health Service number (a unique identifier for each person receiving medical care in the United Kingdom). These data sources were also linked with data on the patient’s date of birth, surname, first name, postal code, and specimen identifiers and sample dates.