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Multicenter Study
. 2022 Oct 11:379:e072065.
doi: 10.1136/bmj-2022-072065.

Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study

Katherine Adams  1 , Jillian P Rhoads  2 , Diya Surie  1 , Manjusha Gaglani  3 , Adit A Ginde  4 , Tresa McNeal  3 , H Keipp Talbot  5   6 , Jonathan D Casey  5 , Anne Zepeski  7 , Nathan I Shapiro  8 , Kevin W Gibbs  9 , D Clark Files  9 , David N Hager  10 , Anne E Frosch  11 , Matthew C Exline  12 , Amira Mohamed  13 , Nicholas J Johnson  14 , Jay S Steingrub  15 , Ithan D Peltan  16 , Samuel M Brown  16 , Emily T Martin  17 , Adam S Lauring  18 , Akram Khan  19 , Laurence W Busse  20 , Abhijit Duggal  21 , Jennifer G Wilson  22 , Steven Y Chang  23 , Christopher Mallow  24 , Jennie H Kwon  25 , James D Chappell  26 , Natasha Halasa  26 , Carlos G Grijalva  6 , Christopher J Lindsell  27 , Sandra N Lester  1 , Natalie J Thornburg  1 , SoHee Park  1 , Meredith L McMorrow  1 , Manish M Patel  1 , Mark W Tenforde  1 , Wesley H Self  28   29 ; Influenza and other Viruses in the AcutelY ill (IVY) Network
Collaborators, Affiliations
Multicenter Study

Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study

Katherine Adams et al. BMJ. .

Abstract

Objective: To compare the effectiveness of a primary covid-19 vaccine series plus booster doses with a primary series alone for the prevention of hospital admission with omicron related covid-19 in the United States.

Design: Multicenter observational case-control study with a test negative design.

Setting: Hospitals in 18 US states.

Participants: 4760 adults admitted to one of 21 hospitals with acute respiratory symptoms between 26 December 2021 and 30 June 2022, a period when the omicron variant was dominant. Participants included 2385 (50.1%) patients with laboratory confirmed covid-19 (cases) and 2375 (49.9%) patients who tested negative for SARS-CoV-2 (controls).

Main outcome measures: The main outcome was vaccine effectiveness against hospital admission with covid-19 for a primary series plus booster doses and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. Vaccine effectiveness analyses were stratified by immunosuppression status (immunocompetent, immunocompromised). The primary analysis evaluated all covid-19 vaccine types combined, and secondary analyses evaluated specific vaccine products.

Results: Overall, median age of participants was 64 years (interquartile range 52-75 years), 994 (20.8%) were immunocompromised, 85 (1.8%) were vaccinated with a primary series plus two boosters, 1367 (28.7%) with a primary series plus one booster, and 1875 (39.3%) with a primary series alone, and 1433 (30.1%) were unvaccinated. Among immunocompetent participants, vaccine effectiveness for prevention of hospital admission with omicron related covid-19 for a primary series plus two boosters was 63% (95% confidence interval 37% to 78%), a primary series plus one booster was 65% (58% to 71%), and for a primary series alone was 37% (25% to 47%) (P<0.001 for the pooled boosted regimens compared with a primary series alone). Vaccine effectiveness was higher for a boosted regimen than for a primary series alone for both mRNA vaccines (BNT162b2 (Pfizer-BioNTech): 73% (44% to 87%) for primary series plus two boosters, 64% (55% to 72%) for primary series plus one booster, and 36% (21% to 48%) for primary series alone (P<0.001); mRNA-1273 (Moderna): 68% (17% to 88%) for primary series plus two boosters, 65% (55% to 73%) for primary series plus one booster, and 41% (25% to 54%) for primary series alone (P=0.001)). Among immunocompromised patients, vaccine effectiveness for a primary series plus one booster was 69% (31% to 86%) and for a primary series alone was 49% (30% to 63%) (P=0.04).

Conclusion: During the first six months of 2022 in the US, booster doses of a covid-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing hospital admissions with omicron related covid-19.

Readers' note: This article is a living test negative design study that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: Funding for this work was provided to all participating sites by the US Centers for Disease Control and Prevention. SMB reports grants from the National Institutes of Health (NIH) and Department of Defense (DoD), participation as the Data Safety Monitoring Board (DSMB) chair for Hamilton Ventilators, and participation as a member of the DSMB for New York University covid-19 clinical trials. JDCasey reports funding from NIH and DoD. SYC reports consulting fees from La Jolla Pharmaceuticals, PureTech Health, and Kiniska Pharmaceuticals, payments or honorariums from La Jolla Pharmaceuticals, and participation on a DSMB for an investigator initiated study conducted at UCLA. JDChappell reports grants and other support from NIH. AD reports consulting fees from ALung technologies. MCE reports payments or honorariums from Abbott Laboratory for sponsored talks. DCF reports consulting fees from Cytovale and participation on a DSMB for Medpace. AEF reports grants from NIH. MG reports grants from CDC, CDC-Abt Associates, CDC-Westat, and Janssen, and a leadership role as co-chair of the Infectious Disease and Immunization Committee of the Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics. KWG reports funding from NIH/National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV-4HT NECTAR trial. AAG reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. MG reports grants from NIH/NHLBI and Agency for Healthcare Research and Quality (AHRQ), consulting fees from Endpoint, a leadership role on the American Thoracic Society (ATS) executive committee and board as well as support from ATS for meeting travel expenses, and participation on a DSMB for Regeneron. CG reports grants from NIH, CDC, Food and Drug Administration, AHRQ, Sanofi, and Syneos Health and consulting fees from Pfizer, Merck, and Sanofi. DNH reports grants from NIH/NHLBI for the ACTIV-4HT NECTAR trial and Incyte and participation as a DSMB chair for the SAFE EVICT Trial of vitamin C in COVID-19. NH reports grants from NIH, Quidel, and Sanofi and honorariums for speaking at the American Academy of Pediatrics (AAP) conference. CLH reports grants from NIH and American Lung Association (ALA) and participation as a DSMB member for iSPY COVID and Team (ANZICS). NJJ reports grants from NIH/NHLBI/NINDS and the University of Washington Royalty Research Fund and payment for expert testimony for the Washington Department of Health. AK reports grants from United Therapeutics, Gilead Sciences, and 4D Medical and a leadership role on the guidelines committee for Chest. JHK reports grants from NIH/NIAID. ASL reports grants from CDC, NIH/NIAID, and Burroughs Wellcome Fund and consulting fees from Sanofi and Roche. CJL reports grants from NIH, DoD, CDC, bioMerieux, Entegrion, Endpoint Health, and AbbVie, patents for risk stratification in sepsis and septic shock, participation on DSMBs for clinical trials unrelated to the current work, a leadership role on the executive committee for the Board of Directors of the Association for Clinical and Translational Science, and stock options in Bioscape Digita. ETM reports grants from Merck, CDC, and NIH and payment/honorariums from the Michigan Infectious Disease Society. TM reports payment/honorariums from the Society of Hospital Medicine. AM reports grants from CDC and NIAID/NIH and participation on a DSMB for the FDA. IDP reports grants from NIH, Janssen, Regeneron, and Asahi Kasei Pharma. TR reports grants from AbbVie, consulting fees from Cumberland Pharmaceuticals, and Cytovale, membership on a DSMB for Sanofi, a leadership role as immediate past president of the American Society of Parenteral and Enteral Nutrition, and stock options in Cumberland Pharmaceuticals. WHS reports receiving the primary funding for this project from the CDC, and research funding from Merck and Gilead Sciences. WBS reports grants from the NIH/NHLBI.

Figures

Fig 1
Fig 1
SARS-CoV-2 sequenced omicron lineages by admission week among 2385 patients with covid-19 (cases), 26 December 2021 to 30 June 2022 (enrollment paused 25-31 January 2022). Case patients not infected with omicron (delta variant, B.1.1.519) confirmed through sequencing were excluded from analysis (n=55) and not displayed in this figure. Of 926 patients with a sequence confirmed omicron related infection, lineage was BA.1 in 351 (37.9%), BA.2 in 497 (53.7%), BA.4 in 26 (2.8%), and BA.5 in 52 (5.6%). Low sequencing totals in late January reflect a pause in IVY network enrollment during 25-31 January 2022 during a protocol update
Fig 2
Fig 2
Pattern of covid-19 vaccine products received across doses. The figure includes patients admitted to hospital with covid-19 (cases) and patients admitted to hospital with acute respiratory symptoms without covid-19 (controls), 26 December 2021 to 30 June 2022 (omicron period)
Fig 3
Fig 3
Vaccine effectiveness among immunocompetent people for prevention of hospital admission with covid-19 in the United States during an omicron dominant period, 26 December 2021 to 30 June 2022. Multivariable logistic regression models were used to determine vaccine effectiveness, with vaccine status as the primary independent variable, case status as the dependent variable, and covariates: admission date (biweekly intervals), age (18-49, 50-64, and ≥65 years), sex, self-reported race and ethnicity, and US Health and Human Services region of the admitting hospital. Models stratified by age group were adjusted using age in years as a continuous variable. Vaccine effectiveness was not calculated for certain subgroups owing to limited sample size. Chronic conditions included cardiovascular, neurologic, pulmonary, gastrointestinal, endocrine, kidney, and hematologic disease; malignancy; immunosuppression not captured in other categories; autoimmune condition; or other condition (sarcoidosis, amyloidosis, or unintentional weight loss ≥4.5 kg (10 lb) in past 90 days). Vaccinated cases and controls counted under BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2 (Janssen/Johnson & Johnson) received homologous product series for all doses. Mixed mRNA category included those receiving any heterologous combination of BNT162b2 and mRNA-1273. Ad26.COV2+mRNA received Ad26.COV2 for their first dose, followed by one dose of any mRNA product. Time between last vaccine dose and symptom onset was stratified into intervals to align with current US recommendations. Hypoxemia within 24 hours of admission was defined as supplemental oxygen use or peripheral oxygen saturation (SpO2) <92%. Analysis by age group was restricted for those completing a primary series plus two boosters to 50 years and older owing to eligibility recommendations. CI=confidence interval
Fig 4
Fig 4
Vaccine effectiveness among immunocompromised patients for prevention of hospital admission with covid-19 in the United States during an omicron dominant period, 26 December 2021 to 30 June 2022. Multivariable logistic regression models were used to determine vaccine effectiveness, with vaccine status as the primary independent variable, case status as the dependent variable, and the following covariates: admission date (biweekly intervals), age (18-49, 50-64, and ≥65 years), sex, self-reported race and ethnicity, and US Health and Human Services region of the admitting hospital. Models stratified by age group were adjusted using age in years as a continuous variable. Vaccine effectiveness was not calculated for certain subgroups owing to limited sample size. Immunocompromising conditions included: active solid organ cancer (active cancer defined as treatment for the cancer or newly diagnosed cancer in past six months), active hematologic cancer (eg, leukemia, lymphoma, or myeloma), HIV infection without AIDS, AIDS, congenital immunodeficiency syndrome, previous splenectomy, previous solid organ transplant, immunosuppressive drugs, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, scleroderma, or inflammatory bowel disease, including Crohn’s disease or ulcerative colitis. Time between last vaccine dose and symptom onset was stratified into intervals to align with current US recommendations. CI=confidence interval
Fig 5
Fig 5
Vaccine effectiveness by predominant omicron lineage (BA.1 or BA.2) for prevention of hospital admissions with covid-19 in the United States during an omicron dominant period, 26 December 2021 to 30 June 2022. Multivariable logistic regression models were used to determine vaccine effectiveness, with vaccine status as the primary independent variable, case status as the dependent variable, and the following covariates: admission date (biweekly intervals), age (18-49, 50-64, and ≥65 years), sex, self-reported race and ethnicity, and US Health and Human Services region of the admitting hospital. CI=confidence interval; IQR=interquartile range
Fig 6
Fig 6
Spaghetti plots of serum antibody concentrations to the SARS-CoV-2 receptor binding domain (anti-RBD) (panel A) and spike protein (anti-spike) (panel C) among healthy adult volunteers before and 2-6 weeks after covid-19 booster doses, 5 October 2021 to 28 January 2022. Targets of the antibody responses were based on proteins from the USA-WA1/2020 strain. Antibody concentrations 2-6 weeks after a primary series are also displayed for the subset of participants with anti-RBD (panel B) and anti-spike (panel D) measurements available from earlier participation in the programme. Each participant is represented with a single line connecting the antibody concentration at each time point. The Pfizer-BioNTech group included 33 participants who received three doses of BNT162b2, including nine who had antibody measurements after full vaccination. The Moderna group included 16 participants who received three mRNA-1273 doses, including seven who had antibody measurements after full vaccination. The Janssen/Johnson & Johnson group included eight participants who received two doses of Ad26.COV2, including three who had antibody measurements after full vaccination. The Janssen/Johnson & Johnson+mRNA group included six participants who received an mRNA vaccine (BNT162b2 or mRNA-1273) booster dose after a single Ad26.COV2 primary series dose, including two who had antibody measurements after the initial Ad26.COV2 dose. The data accompanying this figure are shown in supplemental table S6. BAU=binding antibody units
See this image and copyright information in PMC

Update of

  • Vaccine Effectiveness of Primary Series and Booster Doses against Omicron Variant COVID-19-Associated Hospitalization in the United States.
    Adams K, Rhoads JP, Surie D, Gaglani M, Ginde AA, McNeal T, Ghamande S, Huynh D, Talbot HK, Casey JD, Mohr NM, Zepeski A, Shapiro NI, Gibbs KW, Files DC, Hicks M, Hager DN, Ali H, Prekker ME, Frosch AE, Exline MC, Gong MN, Mohamed A, Johnson NJ, Srinivasan V, Steingrub JS, Peltan ID, Brown SM, Martin ET, Monto AS, Lauring AS, Khan A, Hough CL, Busse LW, Ten Lohuis CC, Duggal A, Wilson JG, Gordon AJ, Qadir N, Chang SY, Mallow C, Rivas C, Babcock HM, Kwon JH, Chappell JD, Halasa N, Grijalva CG, Rice TW, Stubblefield WB, Baughman A, Lindsell CJ, Hart KW, Lester SN, Thornburg NJ, Park S, McMorrow ML, Patel MM, Tenforde MW, Self WH. Adams K, et al. medRxiv [Preprint]. 2022 Jun 14:2022.06.09.22276228. doi: 10.1101/2022.06.09.22276228. medRxiv. 2022. Update in: BMJ. 2022 Oct 11;379:e072065. doi: 10.1136/bmj-2022-072065. PMID: 35734090 Free PMC article. Updated. Preprint.

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