We used a test-negative case-control design to estimate the efficacy of the vaccine against symptomatic Covid-19 caused by the omicron variant compared to the delta variant in persons 18 years of age or older.17 The odds of vaccination in people with symptomatic, PCR-positive cases of SARS-CoV-2 infection were compared with those in symptomatic people who tested negative for SARS-CoV-2 in England.
Covid-19 test data
PCR testing for SARS-CoV-2 in the UK is performed by hospitals and public health laboratories (Pillar 1) as well as by community tests (Pillar 2). Pillar 2 testing is available to anyone with symptoms consistent with Covid-19 (high temperature, new persistent cough or loss or change in sense of smell or taste), anyone who is the contact person for a person with a confirmed case, nursing home staff and residents, and individuals with a positive rapid lateral flow antigen test. Lateral flow tests are freely available to all members of the population for regular home tests. Data on all positive PCR and lateral flow tests and on negative column 2 PCR tests from individuals with a date of onset of Covid-19 symptoms after 25 November 2020 were extracted until 12 January 2022 (fig S1 i Supplementary appendices, available in full text of this article at NEJM.org). Individuals who reported symptoms and were tested in pillar 2 between November 27, 2021 and January 12, 2022, were included in the analysis.
All negative tests taken within 7 days of a previous negative test, and all negative tests for which the symptom onset date was within the 10 days following a previous symptom onset date of a negative test, were dropped because these probably represented the same episode. Negative tests taken within 21 days before a subsequent positive test were also excluded because the chances were high that these were false negatives. Positive and negative tests within 90 days of a previous positive test were also excluded; However, when participants later had positive tests within 14 days after a positive test, PCR testing and testing from symptomatic individuals were preferred. For individuals who had more than one negative test, one test was selected at random during the study period. Data were limited to individuals who had reported symptoms and provided a symptom onset date within the 10 days prior to the test to account for reduced PCR susceptibility beyond this period in an infection event. Only positive tests with sequencing or genotype information or spike gene information (S) target-negative status (indicative of probable omicron infection) was included in the final analysis. A small number of positive tests were excluded when sequencing showed neither the delta nor the omicron variant. Finally, only samples obtained on 27 November 2021 or later were kept for analysis because this corresponded to the period in which S target-negative status was predictable for the omicron variant.
The National Immunization Management System (NIMS) contains demographics of all persons resident in England who are registered with a general practitioner in that country and used to record all Covid-19 vaccinations.29 NIMS was accessed on 18 January 2022 for dates of vaccination and vaccine manufacturer, sex, date of birth, race or ethnic group and address of residence. Addresses were used to determine the index of multiple deprivations (a national indication of the level of deprivation based on small geographic residences, assessed in quintiles) and were also linked to Care Quality Commission-registered nursing homes using the unique property reference number. Data on geographic region (NHS region), clinical risk group status, status of being in a clinically extremely vulnerable group, and health and social worker status were also extracted from NIMS. Clinical risk groups included a number of chronic conditions as described in the Green Paper,30 whereas the clinically extremely vulnerable group included individuals considered to have the highest risk of severe Covid-19, including those with immunosuppressed conditions and those with severe respiratory disease.31 Booster doses were identified as a third dose given at least 175 days after a second dose and administered after September 13, 2021. Individuals with four or more doses of vaccine, a heterologous primary schedule, or less than 19 days between their first dose and second dose were excluded.
Identification of variants and allocation to cases
Sequencing of PCR-positive samples was performed through a network of laboratories, including the Wellcome Sanger Institute. Whole genome sequences were assigned to UK Health Security Agency’s definitions of mutations based on mutations.32.33 S target status in PCR testing is an alternative approach to identifying each variant because the omicron variant has been associated with S target-negative results on PCR test with the TaqPath assay, whereas the delta variant almost always has one S goal-positive result.26 Approximately 40% of Pillar 2 community testing in the UK is performed by laboratories using the TaqPath analysis (Thermo Fisher Scientific). Cases were defined as being due to the delta or omicron variant on the basis of whole genome sequencing, genotyping or S target status, where sequencing is prioritized, followed by genotyping. When subsequent positive tests within 14 days included sequencing or genotype information or information about S goal-negative status, this information was used to classify the variant. A priori we considered it S target-negative status would be used to define the omicron variant when the variant accounted for at least 80% of S goal-negative cases. From 10 January 2022, delta cases were only identified by sequencing and genotyping because the positive predictive value of S goal-negative status to identify the delta variant had decreased and could no longer be used.
Test data were linked to NIMS on 18 January 2021 through combinations of the unique individual NHS number, date of birth, surname, first name and postcode using deterministic linking. A total of 91.8% of the eligible tests could be linked to NIMS.
Logistic regression was used where the PCR test result as the dependent variable and case participants were those who tested positive (stratified in separate analyzes as being infected with either the omicron or delta variant), and controls were those who tested negative. Vaccination status was included as an independent variable, and efficacy was defined as 1 minus the odds of vaccination in the case of participants, divided by the odds of vaccination in controls.
Vaccine efficacy was adjusted in logistic regression models for age (18 to 89 years at 5-year intervals, then all ≥90 years), sex, multiple deprivation index (quintile), race or ethnic group, history of foreign travel, geographical region, period ( test day), health and social worker status, clinical risk group status, status of being in a clinically extremely vulnerable group and previously tested positive. These factors were all considered as potential confounders and were therefore included in all models.
Assays were stratified according to primary immunization sequence (ChAdOx1 nCoV-19, BNT162b2 or mRNA-1273 vaccine). Any heterologous primary schemas were excluded.
Vaccine efficacy was assessed for each primary course at intervals of 2 to 4, 5 to 9, 10 to 14, 15 to 19, 20 to 24 and 25 or more weeks after the second dose. Vaccine efficacy was assessed at 2 to 4, 5 to 9 and 10 or more weeks after a BNT162b2 or mRNA-1273 booster after a ChAdOx1 nCoV-19 or BNT162b2 primary course. In addition, the ChAdOx1 nCoV-19 booster was evaluated after a ChAdOx1 nCoV-19 primary course in these post-vaccination intervals. In subjects with a primary mRNA-1273 course, vaccine efficacy was assessed following BNT162b2 or mRNA-1273 booster vaccines at 1 week and after 2 to 4 weeks.