Study design
We used two approaches to assess the effect of vaccination on the Delta variant. First, we used a test-negative case-control design to estimate the effectiveness of the vaccine against symptomatic disease caused by the Delta variant compared to the Alpha variant over the period that the Delta variant was circulating . This approach has been extensively described elsewhere.10 In brief, we compared the vaccination status in people with symptomatic Covid-19 to the vaccination status in people who reported symptoms but had a negative test. This approach helps control biases related to health-oriented behavior, access to testing, and case identification.
For the secondary analysis, the proportion of people with cases caused by the delta variant was estimated relative to the main circulating virus (the alpha variant) according to vaccination status. The underlying assumption was that if the vaccine had some efficacy and were equally effective against each variant, a similar proportion of cases would be expected in both variants in unvaccinated and vaccinated people. If, on the other hand, the vaccine were less effective against the delta variant than against the alpha variant, it would be expected that the delta variant would make up a higher proportion of cases that occur more than 3 weeks after vaccination than in unvaccinated people. Details of this analysis are described in Section S1 of the Supplementary Appendix, available with the full text of this article on NEJM.org. The authors vouch for the correctness and completeness of the data as well as for the adherence to the protocol of the study.
Data sources
Vaccination status
Data on all people in England who have been vaccinated with Covid-19 vaccines are available in a national vaccination registry (the National Immunization Management System). Data on vaccinations received up to May 16, 2021, including the date of receipt of each vaccine dose and vaccine type, was extracted on May 17, 2021. Vaccination status was categorized as receiving a vaccine dose in people who experienced symptoms 21 days or more after receiving the first dose up to the day before the second dose, as well as people who had symptoms 14 days or more after receiving the second dose Dose occurred as when receiving the second dose and when receiving the first or second dose in people who have symptoms 21 days or more after receiving the first dose (including any period after receiving the second dose).
SARS-CoV-2 tests
Polymerase chain reaction (PCR) tests for SARS-CoV-2 are performed in the UK by hospitals and public health laboratories, as well as community testing using drive-through tests or at-home tests that are available on those with symptoms Corresponding to Covid-19 (high temperature, new persistent cough, or loss or change in sense of smell or taste). Data was extracted on all positive PCR tests between October 26, 2020 and May 16, 2021. For the test-negative-case-control analysis, data on all recorded negative community tests in persons who reported symptoms were also extracted. Children who were younger than 16 on March 21, 2021 were excluded. Data were limited to people who reported symptoms and only included people who were tested within 10 days of the onset of symptoms to take into account the decreased sensitivity of the PCR tests beyond this period
Identification of the variant
Whole genome sequencing was used to identify the delta and alpha variants. The proportion of all positive samples that were sequenced rose from around 10% in February 2021 to around 60% in May 2021.4 Sequencing takes place in a network of laboratories, including the Wellcome Sanger Institute, where a high proportion of samples have been tested , and sequences of the entire genome are mapped to Public Health England’s Definitions of Variants on the basis of mutations. 26
The spike gene target status in PCR was used as a second approach to identify 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 it was found that the alpha variant was associated with a negative test of the S target, so that the S target negative status was subsequently used as a proxy to identify the variant. The alpha variant accounts for between 98% and 100% of the S-Target negative results in England. Among the 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% of the samples in May (as of May 12, 2021) .4 For the test-negative case-control analysis included only samples tested in laboratories with the TaqPath assay.
Data link
The three sources of data described above have been linked to the use of the National Health Service number (a unique identifier for each person receiving medical care in the UK). These data sources were also linked to data on the patient’s date of birth, surname, first name, zip code, sample identifiers, and sample data.
Covariates
Several covariates, which may be related to the likelihood that a vaccine will be offered or accepted, and the risk of exposure to Covid-19 or specifically to one of the variants analyzed, were also extracted 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 degree of deprivation based on small geographic areas, rated 27 in quintiles), race or ethnic group, nursing home residence status , History of international travel (i.e. outside the UK or Ireland), geographic region, time period (calendar week), status of health and social worker and status of a clinically extremely vulnerable group.28 In addition, for the test negative case-control analysis, History of SARS-CoV-2 infection prior to the start of the vaccination program was included. Traveled was anyone who, at the time of requesting a test, reported having traveled outside of the UK and Ireland in the last 14 days, or was tested in a quarantine hotel or quarantine at home. Postal codes were used to determine the multiple deprivation index and unique property reference numbers were used to identify nursing homes. 29
Statistical analysis
For the test-negative case-control analysis, a logistic regression was used to estimate the probability of a symptomatic, PCR-confirmed Covid-19 case in vaccinated persons compared to unvaccinated persons (controls). The cases were identified as delta variants by sequencing or were S-target positive in the TaqPath PCR assay. The cases were identified as alpha variant by sequencing or were S-target negative in the TaqPath PCR assay.
If a person tested positive multiple times (which can represent a single episode of the disease) within 90 days, only the first positive test was included. A maximum of three randomly selected negative test results were included per person. Negative tests where the sample was taken within 3 weeks of a positive result or after a positive result could have been false negative; therefore these have been excluded. Tests performed within 7 days of a previous negative result were also excluded. Individuals who previously tested positive before the analysis period were also excluded to assess the effectiveness of the vaccine in highly susceptible individuals. As in previous test-negative case-control analyzes, all covariates were included in the model, taking into account the calendar week as a factor and without any interaction with the region.
With regard to the S-target positive or negative status, only persons who tested positive on the other two PCR gene targets were included. The assignment to the delta variant on the basis of the S-target status was limited to the week from April 12, 2021 in order to aim for a high specificity of the S-target-positive test for the delta variant
The efficacy of the vaccine for the first dose was estimated in people with a date of onset of symptoms 21 days or more after receiving the first dose of the vaccine, and the vaccine effect for the second dose was estimated in people with a date of onset of symptoms of. estimated 14 days or more after receiving the second dose. A comparison was made between those who had not been vaccinated and those who had symptoms 4 to 13 days after vaccination to account for differences in the underlying risk of infection. The period from the day of vaccine administration (day 0) to day 3 has been excluded, as the reactogenicity of the vaccine can lead to an increase in test results which falsify the results, as previously described
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