Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants

Abstract

Importance: Assessing COVID-19 vaccine performance against the rapidly spreading SARS-CoV-2 Omicron variant is critical to inform public health guidance.

Objective: To estimate the association between receipt of 3 doses of Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 vaccine and symptomatic SARS-CoV-2 infection, stratified by variant (Omicron and Delta).

Design, setting, and participants: A test-negative case-control analysis among adults 18 years or older with COVID-like illness tested December 10, 2021, through January 1, 2022, by a national pharmacy-based testing program (4666 COVID-19 testing sites across 49 US states).

Exposures: Three doses of mRNA COVID-19 vaccine (third dose ≥14 days before test and ≥6 months after second dose) vs unvaccinated and vs 2 doses 6 months or more before test (ie, eligible for a booster dose).

Main outcomes and measures: Association between symptomatic SARS-CoV-2 infection (stratified by Omicron or Delta variants defined using S-gene target failure) and vaccination (3 doses vs unvaccinated and 3 doses vs 2 doses). Associations were measured with multivariable multinomial regression. Among cases, a secondary outcome was median cycle threshold values (inversely proportional to the amount of target nucleic acid present) for 3 viral genes, stratified by variant and vaccination status.

Results: Overall, 23 391 cases (13 098 Omicron; 10 293 Delta) and 46 764 controls were included (mean age, 40.3 [SD, 15.6] years; 42 050 [60.1%] women). Prior receipt of 3 mRNA vaccine doses was reported for 18.6% (n = 2441) of Omicron cases, 6.6% (n = 679) of Delta cases, and 39.7% (n = 18 587) of controls; prior receipt of 2 mRNA vaccine doses was reported for 55.3% (n = 7245), 44.4% (n = 4570), and 41.6% (n = 19 456), respectively; and being unvaccinated was reported for 26.0% (n = 3412), 49.0% (n = 5044), and 18.6% (n = 8721), respectively. The adjusted odds ratio for 3 doses vs unvaccinated was 0.33 (95% CI, 0.31-0.35) for Omicron and 0.065 (95% CI, 0.059-0.071) for Delta; for 3 vaccine doses vs 2 doses the adjusted odds ratio was 0.34 (95% CI, 0.32-0.36) for Omicron and 0.16 (95% CI, 0.14-0.17) for Delta. Median cycle threshold values were significantly higher in cases with 3 doses vs 2 doses for both Omicron and Delta (Omicron N gene: 19.35 vs 18.52; Omicron ORF1ab gene: 19.25 vs 18.40; Delta N gene: 19.07 vs 17.52; Delta ORF1ab gene: 18.70 vs 17.28; Delta S gene: 23.62 vs 20.24).

Conclusions and relevance: Among individuals seeking testing for COVID-like illness in the US in December 2021, receipt of 3 doses of mRNA COVID-19 vaccine (compared with unvaccinated and with receipt of 2 doses) was less likely among cases with symptomatic SARS-CoV-2 infection compared with test-negative controls. These findings suggest that receipt of 3 doses of mRNA vaccine, relative to being unvaccinated and to receipt of 2 doses, was associated with protection against both the Omicron and Delta variants, although the higher odds ratios for Omicron suggest less protection for Omicron than for Delta.

Figure 1.. Inclusion Criteria for a Case-Control Study of Association Between 3 Doses of COVID-19 mRNA Vaccine and Symptomatic SARS-CoV-2 Infection Caused by the Omicron or Delta Variants

Nucleic acid amplification tests (NAATs) were from the Increasing Community Access to Testing platform. EUA indicates Emergency Use Authorization. ^aNine tests were removed because of reported ages older than 100 years. ^bOf all tests with positive results, 17 620 were randomly selected for whole-genome sequencing and used to perform internal validation of S-gene target failure as a marker for the Omicron variant (eTable 1 in the Supplement). This included 4905 tests also included in the main case-control analysis. ^cDuring online registration for SARS-CoV-2 testing, individuals self-reported their COVID-19 vaccination status, including the number of doses (up to 4), product, and month and year of receipt for each dose. Vaccination data were considered incomplete if the number of doses reported did not match the products and dates reported. ^dThese 17 177 samples were used for the main case-control analysis that compared vaccination status between Omicron and Delta cases and SARS-CoV-2–negative controls. This included 2048 tests also included in the internal validation of S-gene target failure as a marker for the Omicron variant. ^eFor vaccine products, individuals could select from 4 options: Johnson & Johnson/Janssen, Pfizer-BioNTech, Moderna, and “other.” ^fPersons were considered eligible for a booster if they reported 2 doses, with a testing date 6 months or more after the second dose, or if they reported 3 doses, with the third dose 6 months or more after the second dose. ^gThese 52 978 samples were used for the main case-control analysis that compared vaccination status between Omicron and Delta cases and SARS-CoV-2–negative controls. This included 2857 tests also included in the internal validation of S-gene target failure as a marker for the Omicron variant.

Figure 2.. Odds Ratios for the Association of 2 Doses of mRNA Vaccine by Months Since Second Dose and Symptomatic SARS-CoV-2 Infection Caused by the Omicron or Delta Variants Among Adults 18 Years or Older Tested in the Increasing Community Access to Testing Platform, December 10, 2021, to January 1, 2022

Shaded regions indicate 95% CIs. Months since second dose reflect 30-day increments since the second dose except for month 0, which only includes days 14 to 30 because tests from persons with second mRNA COVID-19 doses received less than 14 days before testing were excluded from the analysis. The total number of cases and controls included at each time point varied by product (total Ns reported below plots). OR indicates odds ratio.

Figure 3.. Cycle Threshold Values for the N, ORF1ab, and S Genes by Variant and Vaccination Status Among SARS-CoV-2–Positive Cases Tested by the TaqPath COVID-19 Combo Kit Assay in the Increasing Community Access to Testing Platform, December 10, 2021, to January 1, 2022

For each plot, from top to bottom, lines in the box represent the 75th percentile, median, and 25th percentile. The whiskers extend to the largest and smallest values up to 1.5 times the interquartile range from the 75th and 25th percentiles, respectively. Data beyond the ends of the whiskers are plotted individually. Unvaccinated (Omicron n = 3412; Delta n = 5044; total n = 8456) were individuals who received zero vaccine doses. Two doses (tested ≥6 months after dose 2) of mRNA vaccine (Omicron n = 7245; Delta n = 4570; total n = 11 815) included vaccination histories BNT162b2/BNT162b2/no third dose, mRNA-1273/mRNA-1273/no third dose, mRNA-1273/BNT162b2/no third dose, and BNT162b2/mRNA-1273/no third dose. Three doses (tested ≥14 days after dose 3, with ≥6 months between doses 2 and 3) of mRNA vaccine (Omicron n = 2441; Delta n = 679; total n = 3120) included vaccination histories BNT162b2/BNT162b2/BNT162b2, mRNA-1273/mRNA-1273/mRNA-1273, BNT162b2/BNT162b2/mRNA-1273, mRNA-1273/mRNA-1273/BNT162b2, mRNA-1273/BNT162b2/BNT162b2, BNT162b2/mRNA-1273/BNT162b2, mRNA-1273/BNT162b2/mRNA-1273, and BNT162b2/mRNA-1273/mRNA-1273. Cycle threshold (Ct) values were compared between 3 doses and unvaccinated, 3 doses and 2 doses, and 2 doses and unvaccinated. Significance testing was performed with a 2-sided Mann-Whitney U test and false-discovery rate–corrected for multiple comparisons. Q < .001 for all comparisons, except for comparing 3 doses vs unvaccinated for N gene for Omicron and for comparing 2 doses vs unvaccinated for the N and ORF1ab genes for Omicron and the S gene for Delta (eTable 2 in the Supplement).