Efficacy of the Covid-19 vaccine against the Omicron variant (B.1.1.529)
We used a test-negative case-control design to estimate vaccine efficacy against symptomatic Covid-19 caused by the omicron variant compared to the delta variant in people 18 years of age or older.17 The chances of vaccination in people with symptomatic cases of PCR-positive SARS-CoV-2 infection were compared to those of symptomatic people who tested negative for SARS-CoV-2 in England.
Covid-19 test data
PCR testing for SARS-CoV-2 in England is carried out by hospital and public health laboratories (Pillar 1) as well as community testing (Pillar 2). Pillar 2 testing is available to anyone with symptoms consistent with Covid-19 (elevated temperature, new continuous cough, or loss or change in sense of smell or taste), anyone who is contact of someone with a confirmed case, care home staff and residents, and people who test positive for rapid lateral flow antigen. Lateral flow tests are freely available to all members of the population for regular home testing. Data on all positive PCR and lateral flow tests and negative Pillar 2 PCR tests of people with a date of onset of Covid-19 symptoms after November 25, 2020 were extracted up to January 12, 2022 ( Fig. S1 in the Supplementary Appendix, available with the full text of this article on NEJM.org). People 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 performed within 7 days of a previous negative test, and all negative tests for which the symptom onset date was within 10 days of a previous symptom onset date for a negative test, were dropped as they probably depicted the same episode. Negative tests taken within 21 days of a subsequent positive test were also excluded as there was a high chance of them being false negatives. Positive and negative tests within 90 days of a previous positive test were also excluded; however, when participants had subsequent positive tests within 14 days of testing positive, preference was given to PCR testing and testing symptomatic people. For people who had more than one negative test, one test was randomly selected during the study period. Data was limited to people who had reported symptoms and gave a date of onset of symptoms within 10 days prior to testing to account for reduced sensitivity of PCR beyond this time during an event infectious. Only positive tests with sequencing or genotyping information or spike gene information (S) target-negative status (indicating probable omicron infection) was included in the final analysis. A small number of positive tests were excluded when sequencing showed neither the delta variant nor the omicron variant. Finally, only samples obtained on or after November 27, 2021 were retained for analysis because this corresponded to the period when S target-negative status was predictive of the omicron variant.
The National Immunization Management System (NIMS) contains demographic information on all people residing in England who are registered with a GP in that country and is used to record all Covid-19 vaccinations.29 The NIMS was searched on January 18, 2022 for dates of vaccination and vaccine manufacturer, gender, date of birth, race or ethnicity, and residential address. The addresses were used to determine the Multiple Deprivation Index (a national indication of the level of deprivation based on small geographic areas of residence, assessed in quintiles) and were also linked to care homes registered by the Quality Commission care using the unique property reference number. Data on geographic region (NHS region), clinical risk group status, clinically extremely vulnerable group status, and health and social care worker status were also extracted from the NIMS. Clinical risk groups included a range of chronic diseases described in the Green Book,30 while the clinically extremely vulnerable group included those considered most at risk of severe Covid-19, including those with immunocompromised conditions and those with severe respiratory illnesses.31 Booster doses were identified as a third dose given at least 175 days after a second dose and given after September 13, 2021. Individuals who received 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 assignment to cases
Sequencing of PCR-positive samples was undertaken by a network of laboratories, including the Wellcome Sanger Institute. Whole genome sequences were assigned to UK Health Security Agency variant definitions based on mutations.32.33 S target status on the PCR test is an alternative approach to identify each variant as the omicron variant has been associated with S negative target results on PCR tests with the TaqPath test, whereas the delta variant almost always has a S target–positive result.26 Around 40% of Pillar 2 community testing in England is carried out by laboratories using the TaqPath test (Thermo Fisher Scientific). Cases were defined as being due to the delta or omicron variant based on whole genome sequencing, genotyping or S target status, with sequencing taking priority, followed by genotyping. When subsequent positive tests within 14 days included sequencing or genotyping information or information on S target-negative status, this information was used to classify the variant. A priori, we considered that S target-negative status would be used to define the omicron variant when the variant was at least 80% of S target-negative cases. From January 10, 2022, delta cases were identified by sequencing and genotyping only because the positive predictive value of S the target-negative status to identify the delta variant had diminished and could no longer be used.
The test data was linked to the NIMS on January 18, 2021, through combinations of the unique individual NHS number, date of birth, surname, first name and postcode with the use of a deterministic link. In total, 91.8% of eligible tests could be linked to NIMS.
Logistic regression was used, with PCR test result as the dependent variable and case participants being those who tested positive (stratified in separate analyzes as being infected with the omicron or delta variant) and controls being those who the test was negative. Vaccination status was included as an independent variable, and efficacy was defined as 1 minus the probability of vaccination in case participants divided by the probability of vaccination in controls.
Vaccine efficacy was adjusted in logistic regression models for age (18–89 in 5-year increments, then everyone ≥ 90), gender, multiple deprivation index (quintile) , race or ethnic group, foreign travel history, geographical location, time period (day of test), status of health and social care workers, status of clinical risk group, status of belonging to a clinically extremely vulnerable group and previous positive test. These factors were all considered potential confounders and were therefore included in all models.
Analyzes were stratified by primary vaccination regimen (ChAdOx1 nCoV-19, BNT162b2, or mRNA-1273 vaccine). All heterologous primary patterns were excluded.
Vaccine efficacy was assessed for each primary course at intervals of 2-4, 5-9, 10-14, 15-19, 20-24, and 25 or more weeks after the second dose. Vaccine efficacy was assessed at 2–4, 5–9, and 10 or more weeks after a BNT162b2 or mRNA-1273 booster after ChAdOx1 nCoV-19 or BNT162b2 primary treatment. Additionally, ChAdOx1 nCoV-19 recall was assessed after a primary ChAdOx1 nCoV-19 cycle within these post-vaccination intervals. In individuals with a primary course of mRNA-1273, vaccine efficacy was assessed after BNT162b2 or mRNA-1273 booster vaccines after 1 week and after 2–4 weeks.