Study the design
We used two approaches to assess the impact of vaccination on the delta variant. First, we used a test-negative case control design to evaluate the efficacy of the vaccine against symptomatic disease caused by the delta variant compared to the alpha variant during the period when the delta variant was circulating. This approach has been described in detail elsewhere.10 Briefly, we compared vaccination status in individuals with symptomatic Covid-19 disease and vaccination in individuals who reported symptoms but tested negative. This approach helps control biases related to health behaviors, access to testing, and case detection.
For secondary analysis, the proportion of individuals with cases caused by the delta variant relative to the major circulating virus (alpha variant) was assessed according to vaccination status. The main 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 and vaccinated individuals. Conversely, if the vaccine was less effective against the delta variant than against the alpha variant, the delta variant is expected to account for a higher proportion of cases occurring 3 weeks after vaccination than among unvaccinated individuals. Details of this analysis are described in Section S1 of the Supplementary Appendix, available in full at NEJM.org. The authors guarantee the accuracy and completeness of the data and the accuracy of the test protocol.
Data on all individuals in England who have been vaccinated with Covid-19 vaccines are in the National Vaccination Register (National Immunization Management System). Vaccination data that occurred before 16 May 2021, including the date of receipt of each dose of vaccine and type of vaccine, were removed on 17 May 2021. Vaccination status was classified as receiving a single dose of vaccine among individuals who began symptoms 21 days or more after receiving the first dose the day before receiving the second dose, as receiving a second dose among individuals who developed symptoms that occurred 14 days or more after receiving the second dose, and as receiving the first or second dose among individuals with symptoms observed 21 days or more after the first dose (including any period after receiving the second dose).
Testing for SARS-CoV-2
Polymerase chain reaction (PCR) testing for SARS-CoV-2 in the United Kingdom is carried out by hospitals and public health laboratories, as well as community testing using travel or home testing, which is available to anyone with Covid-19-compliant symptoms. (fever, new persistent cough or loss or change of smell or taste). Data on all positive PCR tests between October 26, 2020 and May 16, 2021 were removed. Data on all reported negative community tests among those who reported symptoms were also removed for test-negative case-control analysis. As of March 21, 2021, children under the age of 16 were excluded. Data were limited to those who reported symptoms and included only those who were tested within 10 days of symptoms to account for the reduced sensitivity of PCR testing after this period.25
Identification of the option
Whole genome sequencing was used to identify delta and alpha variants. The share of all positive samples that was tracked increased from about 10% in February 2021 to about 60% in May 2021.4 Sequencing is performed in a network of laboratories, including the Wellcome Sanger Institute, where a large proportion of samples have been tested, and sequences of entire genomes are assigned to determine variants of Public Health England variants based on mutations.26
As a second approach, the target status of the Spike gene on PCR was used to identify each variant. The laboratories used TaqPath analysis (Thermo Fisher Scientific) to test for three gene targets: spike (S), nucleocapsid (N) and open the reading frame 1ab (ORF1ab). In December 2020, it was noted that the alpha variant is associated with negative testing for S goal, therefore S the target-negative status was later used as a proxy to identify the variant. The alpha version accounts for 98% to 100% S target-negative results in England. Among the sequenced samples that gave a positive result on S 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 analysis of the negative case-control test, only samples that were tested in laboratories using TaqPath analysis were included.
The three data sources described above were related to the use of the National Health Service number (a unique identifier for each person receiving health care in the UK). These data sources were also associated with the patient’s date of birth, last name, first name, zip code, sample identifiers, and sample dates.
Several covariates that may be associated with the likelihood of being offered or receiving the vaccine and the risk of exposure to Covid-19, or in particular any of the options analyzed, were also removed from the National Immunization Management System and test data. These data included age (in 10-year age groups), gender, multiple deprivation index, a national indicator of the level of deprivation based on small geographical areas of residence,27 assessed in quintiles), race or ethnicity, home residence status, travel history (ie, outside the United Kingdom or Ireland), geographic region, period (calendar week), medical and social worker status, and status in a clinically extremely vulnerable group .28 In addition, a history of SARS-CoV-2 infection before the start of the vaccination program was included to analyze the negative case-control test. Individuals were considered to be traveling if, at the time of the request for testing, they reported having traveled outside the United Kingdom and Ireland during the previous 14 days, or if they had been tested in a quarantine hotel or during quarantine at home. Postal codes were used to determine the index of multiple deprivation, and unique control numbers were used to identify care homes.29
To analyze the negative case-control test, logistic regression was used to assess the chances of having a symptomatic, PCR-confirmed case of Covid-19 among vaccinated individuals compared to unvaccinated (control). Cases were identified as having a delta variant, by sequence, or if they were S target positive for TaqPath PCR analysis. Cases were identified as having an alpha variant by sequencing or if they were S goal is negative in TaqPath PCR analysis.
If a person tested positive repeatedly on a 90-day period (which may be one episode of the disease), only the first positive test was included. A maximum of three randomly selected negative test results were included for each person. Negative tests in which the sample was obtained within 3 weeks before or after a positive result could be false negative; therefore, they were excluded. Tests performed within 7 days after the previous negative result were also excluded. Individuals who previously had positive results prior to the analysis period were also excluded to evaluate the efficacy of the vaccine in fully susceptible individuals. All covariates were included in the model, as was done with previous test negative case-control analyzes, with the calendar week included as a factor and without interaction with the region.
Regarding S positive-target or negative status, only individuals who tested positive for the other two PCR gene targets were included. Assignment to the delta-based variant S the status of the target was limited to the week starting from April 12, 2021, and further in order to achieve high specificity S target-positive testing for the delta variant.4
The efficacy of the first dose vaccine was evaluated in individuals with a symptom date of 21 days or more after receiving the first dose of the vaccine, and the effects of the second dose vaccine were evaluated in individuals with a symptom onset date of 14 days or more after the second dose. Comparisons were made with unvaccinated individuals and individuals who developed symptoms within 4-13 days of vaccination to help account for differences in the main risk of infection. The period from the day of vaccine administration (day 0) to day 3 was excluded, as reactogenicity to the vaccine may lead to increased testing, which precedes the results, as described previously.10