Effectiveness of Homologous and Heterologous COVID-19 Booster Doses Following 1 Ad.26.COV2.S (Janssen [Johnson & Johnson]) Vaccine Dose Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults — VISION Network, 10 States, December 2021–March 2022

CDC recommends that all persons aged ≥18 years receive a single COVID-19 vaccine booster dose ≥2 months after receipt of an Ad.26.COV2.S (Janssen [Johnson & Johnson]) adenovirus vector-based primary series vaccine; a heterologous COVID-19 mRNA vaccine is preferred over a homologous (matching) Janssen vaccine for booster vaccination. This recommendation was made in light of the risks for rare but serious adverse events following receipt of a Janssen vaccine, including thrombosis with thrombocytopenia syndrome and Guillain-Barré syndrome^† (1), and clinical trial data indicating similar or higher neutralizing antibody response following heterologous boosting compared with homologous boosting (2). Data on real-world vaccine effectiveness (VE) of different booster strategies following a primary Janssen vaccine dose are limited, particularly during the period of Omicron variant predominance. The VISION Network^§ determined real-world VE of 1 Janssen vaccine dose and 2 alternative booster dose strategies: 1) a homologous booster (i.e., 2 Janssen doses) and 2) a heterologous mRNA booster (i.e., 1 Janssen dose/1 mRNA dose). In addition, VE of these booster strategies was compared with VE of a homologous booster following mRNA primary series vaccination (i.e., 3 mRNA doses). The study examined 80,287 emergency department/urgent care (ED/UC) visits^¶ and 25,244 hospitalizations across 10 states during December 16, 2021–March 7, 2022, when Omicron was the predominant circulating variant.** VE against laboratory-confirmed COVID-19–associated ED/UC encounters was 24% after 1 Janssen dose, 54% after 2 Janssen doses, 79% after 1 Janssen/1 mRNA dose, and 83% after 3 mRNA doses. VE for the same vaccination strategies against laboratory-confirmed COVID-19–associated hospitalizations were 31%, 67%, 78%, and 90%, respectively. All booster strategies provided higher protection than a single Janssen dose against ED/UC visits and hospitalizations during Omicron variant predominance. Vaccination with 1 Janssen/1 mRNA dose provided higher protection than did 2 Janssen doses against COVID-19–associated ED/UC visits and was comparable to protection provided by 3 mRNA doses during the first 120 days after a booster dose. However, 3 mRNA doses provided higher protection against COVID-19–associated hospitalizations than did other booster strategies during the same time interval since booster dose. All adults who have received mRNA vaccines for their COVID-19 primary series vaccination should receive an mRNA booster dose when eligible. Adults who received a primary Janssen vaccine dose should preferentially receive a heterologous mRNA vaccine booster dose ≥2 months later, or a homologous Janssen vaccine booster dose if mRNA vaccine is contraindicated or unavailable. Further investigation of the durability of protection afforded by different booster strategies is warranted.

VISION Network methods have been previously published (3). Across 306 ED/UC clinics and 164 hospitals from 10 states, all medical encounters among adults aged ≥18 years with a COVID-19–like illness diagnosis^†† who had received molecular testing (primarily with reverse transcription–polymerase chain reaction) for SARS-CoV-2 during the 14 days before through 72 hours after the medical encounter were considered eligible. The study period began on the earliest day the Omicron variant accounted for ≥50% of sequenced isolates at each site based on state and national surveillance data (state range = December 16–26, 2021). Vaccination status was categorized based on number and type of vaccine doses received (1 Janssen dose, 2 Janssen doses, 1 Janssen/1 mRNA dose, and 3 mRNA doses^§§). Patients with no record of vaccination were considered unvaccinated. Because a booster dose following a primary Janssen dose was recommended on October 15, 2021, to ensure accurate comparisons across booster strategies, patients vaccinated with a booster dose >120 days before the index date^¶¶ were excluded. In addition, patients were excluded if they 1) received only 1 or 2 primary mRNA vaccine doses or >3 mRNA vaccine doses, or received >2 mRNA doses following a primary Janssen dose; 2) received the first Janssen dose 1–13 days earlier or a booster dose 1–6 days earlier; or 3) received a booster dose following a primary Janssen dose earlier than the recommended interval (<2 months after dose 1) or an mRNA booster dose earlier than the recommended interval (<5 months after dose 2).***

Using a test-negative design, investigators estimated VE by comparing the odds of a positive SARS-CoV-2 test result between vaccinated and unvaccinated patients using multivariable logistic regression models (3,4). Models were adjusted using inverse propensity to be vaccinated weights (calculated separately for each VE estimate) and with age, calendar week of index date, geographic area, local virus circulation (percentage of SARS-CoV-2–positive results from testing within the counties surrounding the facility on the date of the encounter), patient comorbidities including immunocompromise^††† (4), and factors not balanced by propensity to be vaccinated included as covariates.^§§§ A statistically significant difference was indicated by nonoverlapping 95% CIs or standardized mean or proportion differences ≥0.2, indicating nonnegligible difference in distributions of vaccination or infection status. All statistical analyses were conducted using R software (version 4.1.2; R Foundation). This study was reviewed and approved by the institutional review boards at participating sites or under a reliance agreement with the Westat, Inc. institutional review board.^¶¶¶

The study included 80,287 encounters among patients with COVID-19–like illness seeking care at ED/UC facilities (Table 1); 64.8% were unvaccinated, 5.6% had received 1 Janssen dose, 0.6% had received 2 Janssen doses, 1.6% had received 1 Jansen/1 mRNA dose, and 27.4% had received 3 mRNA doses. Among booster strategies, the median interval between receipt of the most recent dose and the ED/UC encounter ranged from 49 to 59 days.

Overall, VE against laboratory-confirmed COVID-19–associated ED/UC encounters was significantly higher among patients who had received any booster dose (range = 54%–83%) compared with those who had received only 1 Janssen dose (24%) (Table 2). Among booster strategies, VE against laboratory-confirmed COVID-19–associated ED/UC encounters was significantly higher among patients who had received 1 Janssen/1 mRNA (79%) or 3 mRNA doses (83%) than among patients who had received 2 Janssen doses (54%).

The study included 25,244 hospitalizations among patients with COVID-19–like illness (Table 3); 61.1% were unvaccinated, 5.7% had received 1 Janssen dose, 0.6% had received 2 Janssen doses, 1.5% had received 1 Janssen/1 mRNA dose, and 31.0% had received 3 mRNA doses. Among booster strategies, the median interval between receipt of the most recent dose and hospitalization ranged from 48 to 59 days.

Overall, VE against laboratory-confirmed COVID-19–associated hospitalization was significantly higher among patients who had received any booster dose (range = 67%–90%) compared with patients who had received 1 Janssen dose (31%) (Table 2). Among booster strategies, VE against hospitalizations was significantly higher among patients who had received 3 mRNA doses (90%). VE against hospitalizations was 78% after 1 Janssen/1 mRNA dose and 67% after 2 Janssen doses; however, CIs overlapped.

Corresponding author: Namrata Prasad, [email protected].

¹Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; ²NewYork-Presbyterian Hospital, New York, New York; ³CDC COVID-19 Emergency Response Team; ⁴Epidemic Intelligence Service, CDC; ⁵Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Salt Lake City, Utah; ⁶Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon; ⁷Westat, Rockville, Maryland; ⁸Baylor Scott & White Health, Temple, Texas; ⁹Texas A&M University College of Medicine, Temple, Texas; ¹⁰Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California Division of Research, Oakland, California; ¹¹HealthPartners Institute, Minneapolis, Minnesota; ¹²School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ¹³Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana; ¹⁴Indiana University School of Medicine, Indianapolis, Indiana; ¹⁵Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana; ¹⁶Division of Child and Adolescent Health, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York; ¹⁷Department of Population and Family Health, Columbia University Mailman School of Public Health, New York, New York; ¹⁸Children’s Minnesota, Minneapolis, Minnesota; ¹⁹Vanderbilt University Medical Center, Nashville, Tennessee.

References

1. Oliver SE, Wallace M, See I, et al. Use of the Janssen (Johnson & Johnson) COVID-19 vaccine: updated interim recommendations from the Advisory Committee on Immunization Practices—United States, December 2021. MMWR Morb Mortal Wkly Rep 2022;71:90–5. https://doi.org/10.15585/mmwr.mm7103a4 PMID:35051137
2. Atmar RL, Lyke KE, Deming ME, et al.; DMID 21-0012 Study Group. Homologous and heterologous Covid-19 booster vaccinations. N Engl J Med 2022;386:1046–57. https://doi.org/10.1056/NEJMoa2116414 PMID:35081293
3. Thompson MG, Stenehjem E, Grannis S, et al. Effectiveness of Covid-19 vaccines in ambulatory and inpatient care settings. N Engl J Med 2021;385:1355–71. https://doi.org/10.1056/NEJMoa2110362 PMID:34496194
4. Embi PJ, Levy ME, Naleway AL, et al. Effectiveness of 2-dose vaccination with mRNA COVID-19 vaccines against COVID-19–associated hospitalizations among immunocompromised adults—nine states, January–September 2021. MMWR Morb Mortal Wkly Rep 2021;70:1553–9. https://doi.org/10.15585/mmwr.mm7044e3 PMID:34735426
5. Mayr FB, Talisa VB, Shaikh O, Yende S, Butt AA. Effectiveness of homologous or heterologous Covid-19 boosters in veterans. N Engl J Med 2022. Epub February 9, 2022. https://doi.org/10.1056/NEJMc2200415 PMID:35139265
6. Ferdinands JM, Rao S, Dixon BE, et al. Waning 2-dose and 3-dose effectiveness of mRNA vaccines against COVID-19–associated emergency department and urgent care encounters and hospitalizations among adults during periods of Delta and Omicron variant predominance—VISION Network, 10 states, August 2021–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:255–63. https://doi.org/10.15585/mmwr.mm7107e2 PMID:35176007

Abbreviations: ED = emergency department; ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; SMD = standardized mean or proportion difference; UC = urgent care.
* Medical events with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using ICD-9 and ICD-10 diagnosis codes. Clinician-ordered molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) for SARS-CoV-2 infection occurring ≤14 days before to <72 hours after admission were included.
^† Vaccination status was categorized based on number and type of vaccine doses received before the medical event index date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the medical event or the admission date if testing only occurred after admission. A primary Janssen vaccine dose was defined as 1 Janssen dose; a homologous booster dose following a primary Janssen dose was defined as 2 Janssen doses; a heterologous booster dose following a primary Janssen dose was defined as 1 Janssen/1 mRNA dose; a homologous booster dose following a primary mRNA series vaccination was defined as 3 mRNA doses.
^§ Partners contributing data on medical events and estimated dates of Omicron variant predominance were in California (December 21), Colorado (December 19), Indiana (December 26), Minnesota and Wisconsin (December 25), New York (December 18), Oregon (December 24), Texas (December 16), Utah (December 24), and Washington (December 24).
^¶ An absolute SMD ≥0.20 indicates a nonnegligible difference in variable distributions between medical events for vaccinated versus unvaccinated patients and for positive versus negative test results. When calculating SMDs for differences in characteristics across COVID-19 vaccination status, investigators calculated SMD as the average of the absolute value of the SMD for unvaccinated versus each vaccination status category individually (1 Janssen, 2 Janssen, 1 Janssen/1 mRNA, and 3 mRNA doses). All SMDs are reported as the absolute SMD.
** ED data at Columbia University Irving Medical Center and HealthPartners exclude encounters that were transferred to an in-network hospital.
^†† Unknown race/ethnicity includes Asian, Native Hawaiian or other Pacific islander, American Indian or Alaska Native, other not listed, and multiple races.
^§§ Underlying respiratory condition at discharge was defined as the presence of ICD-9 and ICD-10 discharge codes for asthma, chronic obstructive pulmonary disease, or other lung disease.
^¶¶ Underlying nonrespiratory condition at discharge was defined as the presence of ICD-9 and ICD-10 discharge codes for heart failure, ischemic heart disease, hypertension, other heart disease, stroke, other cerebrovascular disease, diabetes type I or II, other diabetes, metabolic disease, clinical obesity, clinically underweight, renal disease, liver disease, blood disorder, immunosuppression, organ transplant, cancer, dementia, neurologic disorder, musculoskeletal disorder, or Down syndrome.
*** Immunocompromise status was defined as the presence of ICD-9 and ICD-10 discharge codes for solid malignancy, hematologic malignancy, rheumatologic or inflammatory disorder, other intrinsic immune condition or immunodeficiency, or organ or stem cell transplant.

Abbreviations: ED = emergency department; UC = urgent care; Ref = referent group; VE = vaccine effectiveness.
* VE was calculated as [1 − odds ratio] x 100%. Odds ratios were estimated using multivariable logistic regression. Models were adjusted using inverse propensity to be vaccinated (weights calculated separately for each VE estimate) and with age, calendar week of index date, geographic area, local virus circulation (percentage of SARS-CoV-2–positive results from testing within the counties surrounding the facility on the date of the encounter), patient comorbidities including immunocompromise, and factors not balanced by propensity to be vaccinated included as covariates. Of the variables included in the propensity score, previous SARS-CoV-2 testing and test positivity were not balanced after applying inverse propensity weights and thus were added to covariates included in the adjusted VE model.
^† Vaccination status was categorized based on number and type of vaccine doses received before the medical event index date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the medical event or the admission date if testing only occurred after admission. A primary Janssen dose was defined as 1 Janssen dose; a homologous booster dose following a primary Janssen dose was defined as 2 Janssen doses; a heterologous booster dose following a primary Janssen dose was defined as 1 Janssen/1 mRNA dose; a homologous booster dose following a primary mRNA series vaccination was defined as 3 mRNA doses.
^§ Medical events with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using ICD-9 and ICD-10 diagnosis codes. Clinician-ordered molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) for SARS-CoV-2 infection occurring ≤14 days before to <72 hours after admission were included.
^¶ Partners contributing data on medical events and estimated dates of Omicron predominance were in California (December 21), Colorado (December 19), Indiana (December 26), Minnesota and Wisconsin (December 25), New York (December 18), Oregon (December 24), Texas (December 16), Utah (December 24), and Washington (December 24).

Abbreviations: ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; SMD = standardized mean or proportion difference.
* Medical events with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using ICD-9 and ICD-10 diagnosis codes. Clinician-ordered molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) for SARS-CoV-2 infection occurring ≤14 days before to <72 hours after admission were included.
^† Vaccination status was categorized based on number and type of vaccine dose received before the medical event index date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the medical event or the admission date if testing only occurred after admission. A primary Janssen vaccine dose was defined as 1 Janssen dose; a homologous booster dose following a primary Janssen dose was defined as 2 Janssen doses; a heterologous booster dose following a primary Janssen dose was defined as 1 Janssen/1 mRNA dose; a homologous booster dose following a primary mRNA series vaccination was defined as 3 mRNA doses.
^§ Partners contributing data on medical events and estimated dates of Omicron variant predominance were in California (December 21), Colorado (December 19), Indiana (December 26), Minnesota and Wisconsin (December 25), New York (December 18), Oregon (December 24), Texas (December 16), Utah (December 24), and Washington (December 24).
^¶ An absolute SMD ≥0.20 indicates a nonnegligible difference in variable distributions between medical events for vaccinated versus unvaccinated patients and for positive versus negative test results. When calculating SMDs for differences in characteristics across COVID-19 vaccination status, investigators calculated the SMD as the average of the absolute value of the SMD for unvaccinated versus each vaccination status category individually (1 Janssen, 2 Janssen, 1 Janssen/1 mRNA, and 3 mRNA doses). All SMDs are reported as the absolute SMD.
** Unknown race/ethnicity includes Asian, Native Hawaiian or other Pacific islander, American Indian or Alaska Native, other not listed, and multiple races.
^†† Underlying respiratory condition at discharge was defined as the presence of ICD-9 and ICD-10 discharge codes for asthma, chronic obstructive pulmonary disease, or other lung disease.
^§§ Underlying nonrespiratory condition at discharge was defined as the presence of ICD-9 and ICD-10 discharge codes for heart failure, ischemic heart disease, hypertension, other heart disease, stroke, other cerebrovascular disease, diabetes type I or II, other diabetes, metabolic disease, clinical obesity, clinically underweight, renal disease, liver disease, blood disorder, immunosuppression, organ transplant, cancer, dementia, neurologic disorder, musculoskeletal disorder, or Down syndrome.
^¶¶ Immunocompromise status was defined as the presence of ICD-9 and ICD-10 discharge codes for solid malignancy, hematologic malignancy, rheumatologic or inflammatory disorder, other intrinsic immune condition or immunodeficiency, or organ or stem cell transplant.