Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant
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 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).
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.
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.
Multiple covariates that may be associated with the likelihood of being offered or accepting a vaccine and the risk of exposure to Covid-19 or specifically to either of the variants analyzed were also extracted from the National Immunisation Management System and the testing data. These data included age (in 10-year age groups), sex, index of multiple deprivation (a national indication of level of deprivation that is based on small geographic areas of residence,27 assessed in quintiles), race or ethnic group, care home residence status, history of foreign travel (i.e., outside the United Kingdom or Ireland), geographic region, period (calendar week), health and social care worker status, and status of being in a clinically extremely vulnerable group.28 In addition, for the test-negative case–control analysis, history of SARS-CoV-2 infection before the start of the vaccination program was included. Persons were considered to have traveled if, at the point of requesting a test, they reported having traveled outside the United Kingdom and Ireland within the preceding 14 days or if they had been tested in a quarantine hotel or while quarantining at home. Postal codes were used to determine the index of multiple deprivation, and unique property-reference numbers were used to identify care homes.29
For the test-negative case–control analysis, logistic regression was used to estimate the odds of having a symptomatic, PCR-confirmed case of Covid-19 among vaccinated persons as compared with unvaccinated persons (control). Cases were identified as having the delta variant by means of sequencing or if they were S target–positive on the TaqPath PCR assay. Cases were identified as having the alpha variant by means of sequencing or if they were S target–negative on the TaqPath PCR assay.
If a person had tested positive on multiple occasions within a 90-day period (which may represent a single illness episode), only the first positive test was included. A maximum of three randomly chosen negative test results were included for each person. Negative tests in which the sample had been obtained within 3 weeks before a positive result or after a positive result could have been false negatives; therefore, these were excluded. Tests that had been administered within 7 days after a previous negative result were also excluded. Persons who had previously tested positive before the analysis period were also excluded in order to estimate vaccine effectiveness in fully susceptible persons. All the covariates were included in the model as had been done with previous test-negative case–control analyses, with calendar week included as a factor and without an interaction with region.
With regard to S target–positive or –negative status, only persons who had tested positive on the other two PCR gene targets were included. Assignment to the delta variant on the basis of S target status was restricted to the week commencing April 12, 2021, and onward in order to aim for high specificity of S target–positive testing for the delta variant.4
Vaccine effectiveness for the first dose was estimated among persons with a symptom-onset date that was 21 days or more after receipt of the first dose of vaccine, and vaccine effects for the second dose were estimated among persons with a symptom-onset date that was 14 days or more after receipt of the second dose. Comparison was made with unvaccinated persons and with persons who had symptom onset in the period of 4 to 13 days after vaccination in order to help account for differences in underlying risk of infection. The period from the day of vaccine administration (day 0) to day 3 was excluded because reactogenicity to the vaccine can cause an increase in testing that biases results, as previously described.10