Study Sample

A total of 103,199 hospitalizations of patients with Covid-19–like illness who were 50 years of age or older were identified by the seven VISION partners; of these hospitalizations, 64,400 (62%) occurred after the dates of age-specific Covid-19 vaccine eligibility and the time required for vaccination records to be updated (Table S3). The hospitalizations occurred during the period from January 1 through June 22, 2021. Among unvaccinated patients who were hospitalized, the median duration from vaccine eligibility to the index date was 39 days (interquartile range, 16 to 70) (Table S4). SARS-CoV-2 testing with a molecular assay ordered by clinicians was conducted for 74% of the patients who were hospitalized (range across network partners, 55 to 99). During the period from January 1 through June 22, a total of 121,709 visits to emergency departments or urgent care clinics for Covid-19–like illness were identified by three partners; 76,220 visits (63%) occurred after vaccine age eligibility and updates to vaccination records (Table S5). Among the patients who visited an emergency department or urgent care clinic, the median duration from vaccine eligibility to the index date was 39 days (interquartile range, 15 to 70); 30% (range, 25 to 41) of these patients were tested by means of molecular assay. Across the partners, 1872 hospitalizations and 1350 emergency department or urgent care clinic visits were excluded because the index dates occurred 1 to 13 days after the patient received the first dose of Covid-19 vaccine and immunity was considered indeterminant.

Table 2. Table 2. Characteristics of the Patients According to SARS-CoV-2 Test Results and Vaccination Status.

Our analytic sample included 41,552 hospitalizations and 21,522 emergency department or urgent care clinic visits; 3% of the hospitalizations and 14% of the emergency department or urgent care clinic visits were repeat medical visits by the same patient (Table 2). Characteristics of the patients are listed in Table 2, and characteristics of the patients according to network partner are provided in Tables S6 through S11. The median age was 74 years (interquartile range, 66 to 82) among hospitalized patients and 70 years (interquartile range, 61 to 78) among those who visited an emergency department or urgent care clinic. Black patients and Hispanic patients accounted for a larger percentage of medical visits in the hospitalization sample (9% and 11%, respectively) than in the emergency department or urgent care sample (4% and 5%); these findings reflect in part the differing demographic characteristics of the network partners that contributed data on emergency department or urgent care clinic visits. The percentage of patients with underlying medical conditions was higher among hospitalized patients than among those who visited an emergency department or urgent care clinic.

Covid-19–Associated Medical Care

We identified 4321 patients with Covid-19 who had laboratory-confirmed SARS-CoV-2 infection among 41,552 patients who were hospitalized (10%; range across network partners, 5 to 21); the remaining 37,231 hospitalized patients (90%) had discharge codes for Covid-19–like illness but were SARS-CoV-2–negative. Laboratory-confirmed SARS-CoV-2 infection was identified in 3251 of 21,522 patients who visited an emergency department or urgent care clinic (15%; range across network partners, 9 to 19); the remaining 18,271 patients who visited an emergency department or urgent care clinic (85%) were SARS-CoV-2–negative (Table 2). The percentage of SARS-CoV-2–positive patients also varied among network partners (Tables S12 and S13).

The percentage of patients with laboratory-confirmed SARS-CoV-2 infection decreased with age among hospitalized patients and among those with emergency department or urgent care clinic visits. In both care settings, the percentage of infected patients was higher among unvaccinated patients and lower among White patients, non-Hispanic patients, and those with chronic nonrespiratory conditions. The numbers of both SARS-CoV-2–positive patients and SARS-CoV-2–negative patients with medical visits on each day are provided in Figures S1 through S10.

Covid-19 Vaccination Status

On the index date, unvaccinated patients composed approximately half the patients who were hospitalized (49%; range across network partners, 26 to 73) or visited an emergency department or urgent care clinic (55%; range, 45 to 65) (Table 2). In both samples, the largest differences between vaccinated and unvaccinated patients were age, network partner, calendar time, and local SARS-CoV-2 circulation on the index date. These same differences were noted when the sample was limited to SARS-CoV-2–positive patients only (Tables S14 and S15). As described in the Supplementary Appendix, the application of inverse propensity-to-be-vaccinated weighting reduced the differences between vaccinated and unvaccinated patients with respect to these factors and other patient characteristics to a standard mean difference of less than 0.2.

Among vaccinated patients, 53.4% of those who were hospitalized and 53.7% of those who visited an emergency department or urgent care clinic had received the BNT162b2 vaccine, 43.3% and 41.6%, respectively, had received the mRNA-1273 vaccine, and 3.3% and 4.7%, respectively, had received the Ad26.COV2.S vaccine. The median days from full vaccination to the index date were similar with the three types of Covid-19 vaccines and with both samples (hospitalization and emergency department or urgent care clinic) (range, 42 to 53). Among the patients who received the BNT162b2 vaccine, the median duration from partial vaccination (one dose) to the index date of hospitalization was 21 days and the median duration from partial vaccination to the index date of an emergency department or urgent care visit was 20 days; among patients who received the mRNA-1273 vaccine, these durations were 26 days and 24 days, respectively. These findings reflected the different dosing schedules of these vaccines.

mRNA-Based Vaccine and Hospitalization Figure 1. Figure 1. Estimated Vaccine Effectiveness against SARS-CoV-2 Infection Leading to Hospitalization or an Emergency Department or Urgent Care Clinic Visit, According to the Type of Vaccine.

Patients who were partially vaccinated with one dose of a messenger RNA (mRNA)–based vaccine received the first dose at least 14 days before the index date for the medical visit and had not received the second dose by the index date. Patients who were partially vaccinated with two doses of an mRNA-based vaccine received the second dose 1 to 13 days before the index date. Fully vaccinated patients received a single dose of the Ad26.COV2.S vaccine or the second dose of an mRNA-based vaccine at least 14 days before the index date. CI denotes confidence interval, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.

Figure 2. Figure 2. Estimated Effectiveness of Full Two-Dose mRNA Vaccination against SARS-CoV-2 Infection Leading to Hospitalization, According to Age, Race or Ethnic Group, and Underlying Medical Conditions.

Among adults who were 50 years of age or older, the effectiveness of full two-dose mRNA-based vaccination (≥14 days after the second dose) was 89% (95% confidence interval [CI], 87 to 91) against laboratory-confirmed SARS-CoV-2 infection leading to hospitalization; the vaccine-effectiveness point estimates were similar (differences, ≤5 percentage points) with the BNT162b2 and mRNA-1273 vaccines (Figure 1 and Figure 2). The effectiveness of full mRNA-based vaccination was 83% (95% CI, 77 to 87) among patients who were at least 85 years of age, 86% (95% CI, 75 to 92) among Black patients, 90% (95% CI, 85 to 93) among Hispanic patients, 90% (95% CI, 88 to 92) among patients with chronic respiratory conditions, and 88% (95% CI, 86 to 90) among patients with chronic nonrespiratory conditions (Figure 2). When the hospital sample was limited to 7283 admissions to an ICU, the effectiveness of full mRNA-based vaccination against laboratory-confirmed SARS-CoV-2 infection leading to ICU admission was 90% (95% CI, 86 to 93) (Table S16).

Patients who were partially vaccinated with one dose of mRNA-based vaccine received the first dose at least 14 days before the index date and had not received the second dose by the index date. Patients who were partially vaccinated with two doses of mRNA-based vaccine received the second dose 1 to 13 days before the index date. Among patients who received an mRNA-based vaccine, the effectiveness of partial one-dose vaccination (≥14 days after the first dose, but without the second dose) was 54% (95% CI, 47 to 61) against SARS-CoV-2 infection leading to hospitalization, and the effectiveness of partial two-dose vaccination (1 to 13 days after the second dose) was 73% (95% CI, 66% to 79). With both the BNT162b2 and mRNA-1273 vaccines, the effectiveness of full vaccination with respect to Covid-19–associated hospitalization was higher than that of partial vaccination (first dose) (with 95% confidence intervals that did not overlap) (Figure 1). A similar pattern of higher vaccine-effectiveness point estimates for full mRNA-based vaccination than for partial mRNA-based vaccination was noted in all stratified analyses (Table S17). The effectiveness after partial vaccination (first dose) was lower with BNT162b2 than with mRNA-1273 (Figure 1).

The estimates of the effectiveness of full mRNA-based vaccination were similar when stratified according to the six network partners that contributed the most data on hospitalizations (range, 82 to 97%); however, heterogeneity was observed among the partners in the estimates of effectiveness of partial vaccination (first dose). Vaccine effectiveness also remained consistent in the other sensitivity analyses (Section S5). Our simulation model suggested that if both misclassification of outcome and of exposure occur, vaccine effectiveness could be underestimated by as much as 10 percentage points, given the rates of clinical testing, percent positivity, and vaccination coverage observed in our hospitalization sample.

Figure 3. Figure 3. Estimated Effectiveness of mRNA-Based Vaccination against SARS-CoV-2 Infection Leading to Hospitalization or an Emergency Department or Urgent Care Visit, According to the Days since the Most Recent Dose Was Administered.

The total number of hospitalizations shown is higher than the total number in the main analysis because this secondary analysis was conducted weeks after the main analysis and incorporated updated information from vaccination records and registries; specifically, an additional 212 hospitalizations among unvaccinated patients and 831 hospitalizations among vaccinated patients with confirmed vaccination status were included.

In secondary analyses, we stratified mRNA-based vaccine exposure according to 14-day intervals after administration (Figure 3) and according to type of vaccine (Table S18). Vaccine effectiveness with respect to Covid-19–associated hospitalization was null 0 to 13 days after the first dose, and vaccine-effectiveness point estimates increased through 55 days after the first dose. Vaccine-effectiveness point estimates for full mRNA-based vaccination remained consistently high (>80%) through at least 112 days after the second dose.

mRNA-Based Vaccine and Emergency Department and Urgent Care Visits Figure 4. Figure 4. Estimated Effectiveness of Full Two-Dose mRNA-Based Vaccination against SARS-CoV-2 Infection Leading to an Emergency Department or Urgent Care Clinic Visit, According to Age, Race or Ethnic Group, and Underlying Medical Conditions.

The effectiveness of full two-dose mRNA-based vaccination was 91% (95% CI, 89 to 93) against laboratory-confirmed SARS-CoV-2 infection leading to emergency department or urgent care clinic visits (Figure 4); the vaccine-effectiveness point estimates were similar (3 percentage points) with the BNT162b2 and mRNA-1273 vaccines (Figure 1). The effectiveness of full mRNA-based vaccination was 84% (95% CI, 73 to 91) among adults who were 85 years of age or older, 95% (95% CI, 84 to 98) among Black patients, 81% (95% CI, 70 to 88) among Hispanic patients, and 90% (95% CI, 86 to 93) and 90% (95% CI, 87 to 92) among patients with chronic respiratory conditions and those with chronic nonrespiratory conditions, respectively (Figure 4). The effectiveness of partial (one-dose) mRNA-based vaccination (both types) against SARS-CoV-2 infection leading to emergency department or urgent care clinic visits was 68% (95% CI, 61 to 74), and the effectiveness of partial (two-dose) vaccination was 80% (95% CI, 73 to 85) (Table S19). With both the BNT162b2 and mRNA-1273 vaccines, the effectiveness of full vaccination against SARS-CoV-2 infection leading to emergency department or urgent care clinic visits was higher than the effectiveness with partial vaccination (one dose) (Figure 1).

In sensitivity analyses, vaccine-effectiveness point estimates for full mRNA-based vaccination against SARS-CoV-2 infection leading to emergency department or urgent care clinic visits ranged from 89 to 97% across the three network partners. Estimates of vaccine effectiveness also remained consistent in other sensitivity analyses (Section S5).

In secondary analyses, vaccine effectiveness against SARS-CoV-2 infection leading to emergency department or urgent care clinic visits was null 0 to 13 days after the first dose, and then vaccine-effectiveness point estimates increased through 55 days after the first dose. Vaccine-effectiveness point estimates for full mRNA-based vaccination remained consistently high (≥86%) through at least 112 days after the second dose (Figure 3). Estimates of effectiveness according to the type of Covid-19 vaccine are provided in Table S20.

Effectiveness of Ad26.COV2.S Vaccine

Estimates of the effectiveness of Ad26.COV2.S vaccine were limited to five network partners with Ad26.COV2.S vaccine recipients (CUIMC, Intermountain Healthcare, KPNC, KPNW, and Regenstrief Institute). These analyses included 11,468 hospitalizations and 8917 emergency department or urgent care clinic visits that occurred after the index date for the first patient who was fully vaccinated with Ad26.COV2.S for each network partner (Figure 1). The effectiveness of the full one-dose Ad26.COV2.S vaccine was 68% (95% CI, 50 to 79) with respect to Covid-19–associated hospitalization; the effectiveness of full vaccination against SARS-CoV-2 infection leading to emergency department or urgent care clinic visits was 73% (95% CI, 59 to 82) (Figure 1).