Abstract
Background
Data on the effectiveness of the 3-dose mRNA-1273 primary series are limited, particularly in comparison to 2 doses. Given suboptimal COVID-19 vaccine uptake among immunocompromised populations, it is important to monitor the effectiveness of fewer than the recommended doses in this population.
Methods
We conducted a matched cohort study at Kaiser Permanente Southern California to evaluate the relative vaccine effectiveness (rVE) of the 3-dose series vs 2 doses of mRNA-1273 in preventing SARS-CoV-2 infection and severe COVID-19 outcomes among immunocompromised individuals.
Results
We included 21,942 3-dose recipients who were 1:1 matched with randomly selected 2-dose recipients (third doses accrued 08/12/2021–12/31/2021, with follow-up through 01/31/2022). Adjusted rVE of 3 vs 2 doses of mRNA-1273 against SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death were 55.0 % (95 % CI: 50.8–58.9 %), 83.0 % (75.4–88.3 %), and 87.1 % (30.6–97.6 %), respectively.
Conclusion
Three doses of mRNA-1273 were associated with a significantly higher rVE against SARS-CoV-2 infection and severe outcomes, compared to 2 doses. These findings were consistent across subgroups of demographic and clinical characteristics, and mostly consistent across subgroups of immunocompromising conditions. Our study highlights the importance of completing the 3-dose series for immunocompromised populations.
Keywords: COVID-19, Infectious disease medicine, Virology, Epidemiology
1. Introduction
Since first identified in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to >6 million deaths [1]. Immunocompromised individuals such as those living with human immunodeficiency virus (HIV) and solid organ transplant (SOT) recipients are at greater risk of developing severe coronavirus disease 2019 (COVID-19) [2], [3], [4]. Several COVID-19 vaccines have received full approval by the US Food and Drug Administration for use in immunocompromised populations. mRNA-based vaccines approved in the United States (U.S.) include mRNA-1273 (SPIKEVAX; Moderna Inc, Cambridge, MA) and BNT162b2 (COMIRNATY; Pfizer Inc, New York, NY, USA; BioNTech Manufacturing GmbH, Mainz, Germany).
Immunogenicity studies following COVID-19 vaccination in immunocompromised populations have demonstrated varying outcomes depending on disease state [5], [6], [7]. Recent meta-analyses in immunocompromised populations demonstrated an increasing seroconversion rate after the second dose of COVID-19 vaccine compared to the first, regardless of immunosuppression status [8], [9]. Collectively, studies suggest that a second and third dose may provide additional protection for immunocompromised patients [9], but may not elicit a robust, durable antibody response for adequate protection against COVID-19 outcomes [7]. For greater protection from COVID-19, the US Centers for Disease Control and Prevention recommends a 3-dose mRNA primary COVID-19 vaccination series in moderate to severely immunocompromised populations [10].
Although some studies have reported the efficacy of 2 or 3 doses of COVID-19 mRNA vaccines in immunocompromised populations, data on the efficacy of COVID-19 vaccines in this population are largely lacking [11], in particular, compared to 2 doses. A US test-negative study of 10,425 hospitalized adults reported lower vaccine effectiveness (VE) of COVID-19 mRNA vaccines against COVID-19 hospitalization in SOT recipients compared to immunocompetent recipients or those who had other immunosuppressive conditions, and substantially greater protection by 3-dose vaccination (VE = 77 %, 95 % confidence interval [CI]: 48–90 %) than 2-dose vaccination only (VE = 29 %, 95 % CI: −19–58) [12]. Similarly, data from US hospitals showed that among 1,077 adults with immunocompromising conditions, 3 doses of any mRNA vaccine (BNT162b2 or mRNA-1273) provided greater protection (VE = 88 %, 95 % CI: 81–93 %) against COVID-19 hospitalization, compared with 2 doses (VE = 69 %, 95 % CI: 57–78 %) [13]. These underscore the importance of continuing to monitor the effectiveness of less than the recommended doses in this immunocompromised population. In addition, a better understanding of the additional protection provided by a third mRNA vaccine dose is critical in this population to inform future booster dose recommendations. Therefore, we conducted a matched cohort study to evaluate the relative VE (rVE) of the 3-dose mRNA-1273 primary series vs 2 doses of mRNA-1273 in preventing SARS-CoV-2 infection and severe COVID-19 outcomes in immunocompromised populations.
2. Methods
2.1. Study setting
The study setting is described in detail in prior publications utilizing similar data [14], [15]. Briefly, Kaiser Permanente Southern California (KPSC) is an integrated health care system providing care to >4.6 million socio-demographically diverse health plan members in Southern California [16]. All health care encounters, including care received outside KPSC, are documented in the electronic health records (EHR) and available for research. Comprehensive EHR data used for this study included demographics, immunizations, diagnoses, hospitalizations, and pharmacy records. KPSC began administering mRNA-1273 on December 18, 2020. COVID-19 vaccinations received outside KPSC were regularly imported into the EHR from external sources, including California Immunization Registry, claims, and member self-report with valid documentation. This study was approved by the KPSC Institutional Review Board.
2.2. Study population
Individuals aged ≥18 years who were KPSC members for ≥12 months prior to index date (allowing a 31-day gap) through 14 days after the index date, and were immunocompromised at index date were included. Those with a documented history of immunocompromising conditions (identified by International Classification of Diseases, Tenth Revision codes, and through registries and pharmacy data) including HIV/AIDS, leukemia/lymphoma, congenital/other immunodeficiencies, asplenia/hyposplenia, hematopoietic stem cell transplant (HSCT)/SOT, and receipt of immunosuppressive medications (Supplementary Tables 1 and 2), were considered immunocompromised [15]. Index date was defined as the date of receipt of the third dose of mRNA-1273 for the 3-dose recipients (“3-dose group”); the same index date was assigned to their matched counterpart who received 2 doses only as of that index date (“2-dose group”) (Supplementary Fig. 1). Those who received a COVID-19 vaccine other than mRNA-1273 prior to index date, received 2 doses of mRNA-1273 <24 days apart, received any COVID-19 vaccine <14 days after the index date, or had a COVID-19 outcome <14 days after the index date were excluded.
Eligible individuals who received 3 doses of mRNA-1273 vaccine ≥24 days apart (4-day grace period allowed prior to the recommended 28-day interval) were included in the 3-dose group. The 2-dose group included eligible individuals who received 2 doses of mRNA-1273 ≥24 days apart as of the index date. Individuals in the 2-dose group were randomly selected and 1:1 matched to individuals in the 3-dose group by age (18–44 years, 45–64 years, 65–74 years, and ≥75 years), sex, race/ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic, Non-Hispanic Asian, and Other/Unknown), and the second dose date. Third doses were accrued from 08/12/2021 to 12/31/2021, with follow-up through 01/31/2022, spanning the Delta and Omicron SARS-CoV-2 variant periods [17].
2.3. Exposure and outcome
Exposure of interest was 2 or 3 doses of mRNA-1273 captured from KPSC’s vaccination records. Primary outcomes were SARS-CoV-2 infection and severe COVID-19 disease (COVID-19 hospitalization and death during COVID-19 hospitalization) [18]. SARS-CoV-2 infection was defined as a positive molecular test or a COVID-19 diagnosis code for both symptomatic and asymptomatic cases. Severe COVID-19 disease included COVID-19 hospitalization and COVID-19 mortality (death during COVID-19 hospitalization). COVID-19 hospitalization was defined as hospitalization with a SARS-CoV-2 positive test or a COVID-19 diagnosis, or a hospitalization occurring ≤7 days after a SARS-CoV-2 positive test and confirmed by pre-determined criteria or manual chart reviews [14]. We considered a SARS-CoV-2 infection incident if there was no evidence of a COVID-19 diagnosis code or SARS-CoV-2 positive test in the 90 days prior. Individuals were followed for COVID-19 outcomes from 14 days after the index date (08/12/2021–12/31/2021) through end of study follow-up (01/31/2022), outcome of interest, or censoring (termination of KPSC membership allowing for a 31-day gap, death, or receipt of an additional COVID-19 vaccine), whichever occurred first. Individuals in the 2-dose group who received an eligible third dose of mRNA-1273 during follow-up were censored and started contributing 3-dose person-time 14 days after their third dose.
2.4. Other variables
Potential confounders were identified a priori based on prior knowledge and literature. Baseline patient and clinical characteristics collected included age, sex, race/ethnicity, socioeconomic status, and pregnancy status. Other variables included Charlson comorbidity score, autoimmune conditions, health care utilization, preventive care, chronic diseases, frailty index [19], history of SARS-CoV-2 molecular test, and immunocompromising sub-conditions.
2.5. Statistical analysis
We described demographic and clinical characteristics of individuals in the 2-dose and 3-dose groups. Categorical variables were compared using the χ2 test (or Fisher’s exact test as appropriate), and continuous variables using the two-sample t-test (or Wilcoxon rank-sum test as appropriate). Absolute standardized differences (ASD) were computed to assess the balance of the distribution of covariates between the two groups. Matching variables and immunocompromising sub-conditions were included in the multivariable models based on scientific relevance, along with other covariates with ASD >0.1 from the list of pre-specified potential confounders. To reduce the loss of statistical power, the missing indicator method was used for covariates with missing data [20], allowing participants with missing covariate data to still be included.
Overall incidence rates (IR) of SARS-CoV-2 infection and severe COVID-19 disease for 3-dose and 2-dose groups were computed. Cumulative incidences were estimated using the Kaplan-Meier method and compared using the log-rank test. Unadjusted and adjusted hazard ratios (HR) and corresponding 95 % confidence intervals (CIs) comparing the 3-dose and 2-dose groups were estimated by Cox proportional hazards regression models. rVE (%) was calculated as (1 – HR) × 100 when HR was ≤1, and ([1/HR] – 1) × 100 when HR was >1. We also computed IR, HR, and rVE of mRNA-1273 vaccine in preventing SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death in the 3-dose and 2-dose groups by the number of months (0-<3 and 3-<6) from 14 days after the index date. All statistical analyses were conducted using SAS software version 9.4, Cary, USA.
3. Results
Our study included 21,942 immunocompromised individuals who received the 3-dose primary series and 21,942 immunocompromised individuals who received 2 doses of mRNA-1273 (Fig. 1 ). Our cohort had a median age of 65 years (interquartile range [IQR] 54–74), was 51 % female and 47 % non-Hispanic White (Table 1 ) and was followed up for up to 5.6 months (mean follow-up 1.8 months; standard deviation [s.d.] 1.3) for SARS-CoV-2 infection. Individuals in the 3-dose group had a higher Charlson comorbidity score and a higher proportion with leukemia/lymphoma, congenital/other immunodeficiencies, asplenia/hyposplenia, and transplant, vs the 2-dose group. Individuals in the 3-dose group also received more preventive care and had a higher number of outpatient/virtual visits in the one year prior to index date, vs the 2-dose group. Other baseline demographic and clinical characteristics were comparable between the two groups. Approximately 40 % of the index dates occurred between August and October 2021; the remaining 60 % occurred in October through December 2021, with the highest number occurring in November 2021 (34 %). Mean time between the second dose and index date was 217.9 days (s.d. 42.1) in the 3-dose group and 217.8 days (s.d. 42.2) in the 2-dose group. A total of 9,064 individuals were censored from the 2-dose group upon receipt of their third dose and began contributing 3-dose person-time 14 days after their third dose of mRNA-1273. No individuals had SARS-CoV-2 infections or COVID-19 hospitalizations during follow-up in both groups.
Fig. 1.
Flow chart for 3-dose and 2-dose mRNA-1273 immunocompromised vaccine cohorts.
Table 1.
Baseline characteristics of the mRNA-1273 3-dose primary series vaccinated and 2-dose vaccinated groups among immunocompromised individuals.
| Characteristics | 3-dose primary series vaccinated | 2-dose vaccinated | Total | Absolute Standardized Difference |
|---|---|---|---|---|
| N = 21,942 | N = 21,942 | N = 43,884 | ||
| Age at index date, years | 0.01 | |||
| Mean (standard deviation) | 62.98 (15.37) | 62.76 (16.08) | 62.87 (15.73) | |
| Median (interquartile range) | 65 (54, 74) | 65 (53, 74) | 65 (54, 74) | |
| Minimum, maximum | 18, 102 | 18, 105 | 18, 105 | |
| Age at index date, years, n (%) | N/A | |||
| 18–44 | 2,904 (13.2 %) | 2,904 (13.2 %) | 5,808 (13.2 %) | |
| 45–64 | 7,706 (35.1 %) | 7,706 (35.1 %) | 15,412 (35.1 %) | |
| 65–74 | 6,148 (28.0 %) | 6,148 (28.0 %) | 12,296 (28.0 %) | |
| ≥75 | 5,184 (23.6 %) | 5,184 (23.6 %) | 10,368 (23.6 %) | |
| Sex, n (%) | N/A | |||
| Female | 11,117 (50.7 %) | 11,117 (50.7 %) | 22,234 (50.7 %) | |
| Male | 10,825 (49.3 %) | 10,825 (49.3 %) | 21,650 (49.3 %) | |
| Race/Ethnicity, n (%) | N/A | |||
| Non-Hispanic White | 10,394 (47.4 %) | 10,394 (47.4 %) | 20,788 (47.4 %) | |
| Hispanic | 6,561 (29.9 %) | 6,561 (29.9 %) | 13,122 (29.9 %) | |
| Non-Hispanic Asian | 2,184 (10.0 %) | 2,184 (10.0 %) | 4,368 (10.0 %) | |
| Non-Hispanic Black | 2,113 (9.6 %) | 2,113 (9.6 %) | 4,226 (9.6 %) | |
| Other/Unknown | 690 (3.1 %) | 690 (3.1 %) | 1,380 (3.1 %) | |
| Body mass indexa, kg/m2, n (%) | 0.05 | |||
| <18.5 | 387 (1.8 %) | 442 (2.0 %) | 829 (1.9 %) | |
| 18.5 - <25 | 6,318 (28.8 %) | 6,203 (28.3 %) | 12,521 (28.5 %) | |
| 25 - <30 | 7,519 (34.3 %) | 7,460 (34.0 %) | 14,979 (34.1 %) | |
| 30 - <35 | 4,241 (19.3 %) | 4,280 (19.5 %) | 8,521 (19.4 %) | |
| 35 - <40 | 1,886 (8.6 %) | 1,872 (8.5 %) | 3,758 (8.6 %) | |
| 40 - <45 | 791 (3.6 %) | 736 (3.4 %) | 1,527 (3.5 %) | |
| ≥45 | 433 (2.0 %) | 461 (2.1 %) | 894 (2.0 %) | |
| Unknown | 367 (1.7 %) | 488 (2.2 %) | 855 (1.9 %) | |
| Smokinga, n (%) | 0.04 | |||
| No | 15,639 (71.3 %) | 15,484 (70.6 %) | 31,123 (70.9 %) | |
| Yes | 6,107 (27.8 %) | 6,176 (28.1 %) | 12,283 (28.0 %) | |
| Unknown | 196 (0.9 %) | 282 (1.3 %) | 478 (1.1 %) | |
| Charlson comorbidity scoreb, n (%) | 0.14 | |||
| 0 | 3,996 (18.2 %) | 5,180 (23.6 %) | 9,176 (20.9 %) | |
| 1 | 3,249 (14.8 %) | 3,401 (15.5 %) | 6,650 (15.2 %) | |
| ≥2 | 14,697 (67.0 %) | 13,361 (60.9 %) | 28,058 (63.9 %) | |
| Frailty indexb, n (%) | 0.06 | |||
| Quartile 1 | 5,296 (24.1 %) | 5,675 (25.9 %) | 10,971 (25.0 %) | |
| Quartile 2 | 5,565 (25.4 %) | 5,407 (24.6 %) | 10,972 (25.0 %) | |
| Quartile 3 | 5,711 (26.0 %) | 5,259 (24.0 %) | 10,970 (25.0 %) | |
| Quartile 4, most frail | 5,370 (24.5 %) | 5,601 (25.5 %) | 10,971 (25.0 %) | |
| Chronic diseasesb, n (%) | ||||
| Diabetes | 5,905 (26.9 %) | 5,770 (26.3 %) | 11,675 (26.6 %) | 0.01 |
| Kidney disease | 5,043 (23.0 %) | 4,537 (20.7 %) | 9,580 (21.8 %) | 0.06 |
| Lung disease | 4,054 (18.5 %) | 3,897 (17.8 %) | 7,951 (18.1 %) | 0.02 |
| Heart disease | 2,430 (11.1 %) | 2,697 (12.3 %) | 5,127 (11.7 %) | 0.04 |
| Liver disease | 2,067 (9.4 %) | 1,844 (8.4 %) | 3,911 (8.9 %) | 0.04 |
| Immunocompromised, n (%) | ||||
| Immunosuppressant medications | 12,916 (58.9 %) | 13,852 (63.1 %) | 26,768 (61.0 %) | 0.09 |
| Leukemia/lymphoma, congenital and other immunodeficiencies, asplenia/hyposplenia | 8,515 (38.8 %) | 7,224 (32.9 %) | 15,739 (35.9 %) | 0.12 |
| HIV/AIDS | 2,648 (12.1 %) | 2,140 (9.8 %) | 4,788 (10.9 %) | 0.07 |
| Hematopoietic stem cell transplant/solid organ transplant | 2,220 (10.1 %) | 1,300 (5.9 %) | 3,520 (8.0 %) | 0.15 |
| Autoimmune conditionsb, n (%) | 6,303 (28.7 %) | 5,487 (25.0 %) | 11,790 (26.9 %) | 0.08 |
| Rheumatoid arthritis, n | 4,123 | 3,493 | 7,616 | |
| Inflammatory bowel disease, n | 873 | 714 | 1,587 | |
| Psoriasis and psoriatic arthritis, n | 1,453 | 1,365 | 2,818 | |
| Multiple sclerosis, n | 120 | 110 | 230 | |
| Systemic lupus erythematosus, n | 523 | 370 | 893 | |
| Pregnant at index date, n (%) | 20 (0.1 %) | 53 (0.2 %) | 73 (0.2 %) | 0.04 |
| 1st trimester, n | 6 | 13 | 19 | |
| 2nd trimester, n | 0 | 12 | 12 | |
| 3rd trimester, n | 14 | 28 | 42 | |
| History of SARS-CoV-2 infectionc, n (%) | 2,029 (9.2 %) | 2,335 (10.6 %) | 4,364 (9.9 %) | 0.05 |
| History of SARS-CoV-2 molecular testc, n (%) | 13,947 (63.6 %) | 14,135 (64.4 %) | 28,082 (64.0 %) | 0.02 |
| Number of outpatient and virtual visitsb, n (%) | 0.15 | |||
| 0 | 49 (0.2 %) | 119 (0.5 %) | 168 (0.4 %) | |
| 1–4 | 1,061 (4.8 %) | 1,510 (6.9 %) | 2,571 (5.9 %) | |
| 5–10 | 4,367 (19.9 %) | 5,183 (23.6 %) | 9,550 (21.8 %) | |
| ≥11 | 16,465 (75.0 %) | 15,130 (69.0 %) | 31,595 (72.0 %) | |
| Number of Emergency Department visitsb, n (%) | 0.09 | |||
| 0 | 16,114 (73.4 %) | 15,304 (69.7 %) | 31,418 (71.6 %) | |
| 1 | 3,492 (15.9 %) | 3,754 (17.1 %) | 7,246 (16.5 %) | |
| ≥2 | 2,336 (10.6 %) | 2,884 (13.1 %) | 5,220 (11.9 %) | |
| Number of hospitalizationsb, n (%) | 0.09 | |||
| 0 | 19,209 (87.5 %) | 18,596 (84.8 %) | 37,805 (86.1 %) | |
| 1 | 1,846 (8.4 %) | 2,112 (9.6 %) | 3,958 (9.0 %) | |
| ≥2 | 887 (4.0 %) | 1,234 (5.6 %) | 2,121 (4.8 %) | |
| Preventive careb, n (%) | 20,182 (92.0 %) | 19,418 (88.5 %) | 39,600 (90.2 %) | 0.12 |
| Medicaid, n (%) | 1,762 (8.0 %) | 1,886 (8.6 %) | 3,648 (8.3 %) | 0.02 |
| Neighborhood median household income, n (%) | 0.03 | |||
| < $40,000 | 975 (4.4 %) | 1,036 (4.7 %) | 2,011 (4.6 %) | |
| $40,000-$59,999 | 4,023 (18.3 %) | 4,247 (19.4 %) | 8,270 (18.8 %) | |
| $60,000-$79,999 | 5,185 (23.6 %) | 5,140 (23.4 %) | 10,325 (23.5 %) | |
| $80,000+ | 11,745 (53.5 %) | 11,498 (52.4 %) | 23,243 (53.0 %) | |
| Unknown | 14 (0.1 %) | 21 (0.1 %) | 35 (0.1 %) | |
| KPSC physician/employee, n (%) | 836 (3.8 %) | 804 (3.7 %) | 1,640 (3.7 %) | 0.01 |
| Concomitant vaccinationd, n (%) | 1,270 (5.8 %) | N/A | N/A | N/A |
| Time between second dose and index date, days | <0.01 | |||
| Mean (standard deviation) | 217.85 (42.12) | 217.79 (42.17) | 217.82 (42.14) | |
| Median (interquartile range) | 222 (193, 246) | 222 (193, 246) | 222 (193, 246) | |
| Minimum, maximum | 28, 339 | 24, 340 | 24, 340 | |
| Time between second dose and index date, days, n (%) | <0.01 | |||
| 24-<150 days | 1,611 (7.3 %) | 1,638 (7.5 %) | 3,249 (7.4 %) | |
| 150-<240 days | 13,226 (60.3 %) | 13,214 (60.2 %) | 26,440 (60.2 %) | |
| ≥240 days | 7,105 (32.4 %) | 7,090 (32.3 %) | 14,195 (32.3 %) | |
| Month of index date, n (%) | N/A | |||
| August 2021 | 2,500 (11.4 %) | 2,500 (11.4 %) | 5,000 (11.4 %) | |
| September 2021 | 3,173 (14.5 %) | 3,173 (14.5 %) | 6,346 (14.5 %) | |
| October 2021 | 3,455 (15.7 %) | 3,455 (15.7 %) | 6,910 (15.7 %) | |
| November 2021 | 7,488 (34.1 %) | 7,488 (34.1 %) | 14,976 (34.1 %) | |
| December 2021 | 5,326 (24.3 %) | 5,326 (24.3 %) | 10,652 (24.3 %) | |
Medical center area not shown (absolute standardized difference = 0.10). There were no differences in the distribution of the vaccinated and unvaccinated individuals across the 19 medical center areas.
Abbreviations. N/A, not applicable; KPSC, Kaiser Permanente Southern California; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Defined in the two years prior to index date.
Defined in the one year prior to index date.
Defined based on all available medical records from March 1, 2020 to index date.
Among subjects with concomitant vaccines received with the third dose: influenza vaccine (90.2 %), PCV13/PPSV23 (3.2 %), Tdap (6.1 %), and other vaccine (5.0 %).
Between 08/12/2021 and 01/31/2022, 1,293 3-dose recipients and 964 2-dose recipients experienced a SARS-CoV-2 infection, with an IR per 1,000 person-years (95 % CI) higher in the 2-dose group (478.9 [449.6–510.1]) vs the 3-dose group (277.9 [263.1–293.4]) (Table 2 ). Similarly, we observed a higher IR for COVID-19 hospitalization per 1,000 person-years for the 2-dose group (42.5 [34.5–52.4]) than the 3-dose group (16.1 [12.8–20.1]). IR for COVID-19 hospital death per 1,000 person-years was 2.9 (1.3–6.4) in the 2-dose group and 0.4 (0.1–1.7) in the 3-dose group. The Kaplan-Meier plots for the 2-dose group demonstrated consistently higher cumulative incidence estimates of SARS-CoV-2 infection, COVID-19 hospitalization, and hospital death, vs the 3-dose group (p <0.0001, log-rank test) (Fig. 2 ). Adjusted rVE of 3 doses vs 2 doses of mRNA-1273 against SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death were 55.0 % (50.8–58.9 %), 83.0 % (75.4–88.3 %), and 87.1 % (30.6–97.6 %), respectively (Table 2). Adjusted rVE point estimates against SARS-CoV-2 infection ranged from 43.0 % to 59.1 % across subgroups of age, sex, race/ethnicity, history of SARS-CoV-2 infection, and comorbidities, and from 6.4 % to 57.3 % across subgroups of immunocompromising conditions (Table 3 ). Adjusted rVE of 3 doses vs 2 doses against SARS-CoV-2 infection was 57.2 % (52.8–61.2 %) in the first 3 months, and 40.2 % (21.6–54.4 %) 3 to 6 months from 14 days after the third dose (Table 4 ). Adjusted rVE of 3 doses vs 2 doses against COVID-19 hospitalization was 86.1 % (78.6–90.9 %) in the first 3 months and 44.5 % (−48.7 to 84.2 %) between 3 and 6 months following the third dose.
Table 2.
Incidence rate and relative vaccine effectiveness of the mRNA-1273 3-dose primary series in preventing SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death among immunocompromised population, with 2-dose vaccinated comparison.
| Outcomes |
3-dose primary series vaccinated |
2-dose vaccinated |
Adjustedarelative vaccine effectiveness % (95 % CI) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| N | Number of cases | Number of person-years | Incidence per 1000 person-years (95 % CI) | N | Number of cases | Number of person-years | Incidence per 1000 person-years (95 % CI) | ||
| SARS-CoV-2 infection | 21,942 | 1,293 | 4,653.64 | 277.85 (263.11–293.41) | 21,942 | 964 | 2,013.03 | 478.88 (449.58–510.08) | 55.0 (50.8–58.9) |
| COVID-19 hospitalization | 21,942 | 76 | 4,727.94 | 16.07 (12.84–20.13) | 21,942 | 88 | 2,070.52 | 42.50 (34.49–52.38) | 83.0 (75.4–88.3) |
| COVID-19 hospital death | 21,942 | 2 | 4,732.71 | 0.42 (0.11–1.69) | 21,942 | 6 | 2,076.18 | 2.89 (1.30–6.43) | 87.1 (30.6–97.6)b |
Abbreviations. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Adjusted for covariates age, sex, race/ethnicity, index date (in months), time between second dose and index date, number of outpatient and virtual visits, preventive care, Charlson comorbidity score, and immunocompromising sub-conditions.
Adjusted for covariates age, sex, index date (in months), time between second dose and index date, and immunocompromising sub-conditions (except HIV/AIDS).
Fig. 2.
Cumulative incidence estimates of SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death in 3-dose and 2-dose mRNA-1273 immunocompromised vaccine cohorts. A. SARS-CoV-2 infection B. COVID-19 hospitalization C. COVID-19 hospital death.
Table 3.
Incidence rate and relative vaccine effectiveness of the mRNA-1273 3-dose primary series in preventing SARS-CoV-2 infection by subgroups among immunocompromised population, with 2-dose vaccinated comparison.
| Characteristics |
3-dose primary series vaccinated |
2-dose vaccinated |
Adjustedarelative vaccine effectiveness % (95 % CI) |
||||||
|---|---|---|---|---|---|---|---|---|---|
| N | Number of cases | Number of person-years | Incidence per 1000 person-years (95 % CI) | N | Number of cases | Number of person-years | Incidence per 1000 person-years (95 % CI) | ||
| Age at index date, years | |||||||||
| 18–44 | 2,904 | 233 | 529.64 | 439.92 (386.91–500.19) | 2,904 | 229 | 322.56 | 709.94 (623.70–808.11) | 49.8 (39.2–58.6) |
| 45–64 | 7,706 | 567 | 1,542.89 | 367.49 (338.46–399.02) | 7,706 | 416 | 696.49 | 597.28 (542.56–657.52) | 56.4 (49.9–62.0) |
| 65–74 | 6,148 | 301 | 1,421.04 | 211.82 (189.19–237.15) | 6,148 | 179 | 548.62 | 326.28 (281.81–377.75) | 56.6 (46.8–64.7) |
| ≥75 | 5,184 | 192 | 1,160.07 | 165.51 (143.68–190.66) | 5,184 | 140 | 445.36 | 314.35 (266.36–370.98) | 58.5 (47.3–67.3) |
| Sex | |||||||||
| Female | 11,117 | 656 | 2,328.98 | 281.67 (260.92–304.07) | 11,117 | 548 | 1,024.33 | 534.98 (492.02–581.70) | 57.8 (52.3–62.7) |
| Male | 10,825 | 637 | 2,324.65 | 274.02 (253.55–296.15) | 10,825 | 416 | 988.7 | 420.75 (382.20–463.19) | 51.9 (44.9–58.1) |
| Race/Ethnicity | |||||||||
| Non-Hispanic White | 10,394 | 473 | 2,306.66 | 205.06 (187.39–224.40) | 10,394 | 345 | 951.34 | 362.65 (326.33–403.01) | 57.3 (50.3–63.4) |
| Hispanic | 6,561 | 539 | 1,301.84 | 414.03 (380.51–450.50) | 6,561 | 428 | 604.58 | 707.93 (643.94–778.28) | 56.1 (49.6–61.8) |
| Non-Hispanic Asian | 2,184 | 124 | 474.88 | 261.12 (218.98–311.37) | 2,184 | 76 | 201.04 | 378.04 (301.92–473.34) | 47.8 (28.9–61.6) |
| Non-Hispanic Black | 2,113 | 118 | 431.74 | 273.31 (228.19–327.36) | 2,113 | 83 | 183.93 | 451.26 (363.91–559.58) | 54.5 (38.0–66.6) |
| History of SARS-CoV-2 infection | |||||||||
| No | 19,913 | 1203 | 4,265.37 | 282.04 (266.54–298.44) | 19,607 | 889 | 1,786.71 | 497.56 (465.91–531.37) | 56.8 (52.6–60.7) |
| Yes | 2,029 | 90 | 388.27 | 231.80 (188.53–285.00) | 2,335 | 75 | 226.32 | 331.39 (264.27–415.55) | 43.0 (20.5–59.1) |
| Pregnant women | 20 | 2 | 3.75 | 532.82 (133.26–2130.46) | 53 | 1 | 6.69 | 149.39 (21.04–1060.51) | Not evaluable |
| Comorbidities | |||||||||
| Diabetes | 5,905 | 393 | 1,310.02 | 299.99 (271.75–331.17) | 5,770 | 253 | 514.38 | 491.85 (434.83–556.35) | 55.9 (47.5–63.0) |
| Kidney disease | 5,043 | 334 | 1,204.89 | 277.20 (249.01–308.59) | 4,537 | 176 | 385.21 | 456.89 (394.14–529.63) | 58.1 (48.1–66.1) |
| Lung disease | 4,054 | 240 | 904.49 | 265.34 (233.81–301.13) | 3,897 | 172 | 338.26 | 508.49 (437.90–590.45) | 59.1 (49.2–67.0) |
| Heart disease | 2,430 | 161 | 542.19 | 296.94 (254.44–346.54) | 2,697 | 126 | 237.86 | 529.73 (444.86–630.79) | 57.9 (45.2–67.6) |
| Liver disease | 2,067 | 147 | 480.92 | 305.66 (260.04–359.29) | 1,844 | 91 | 162.02 | 561.65 (457.33–689.75) | 56.2 (41.3–67.3) |
| Immunocompromising subgroups | |||||||||
| Immunosuppressant medications | 12,916 | 835 | 2,789.59 | 299.33 (279.70–320.33) | 13,852 | 675 | 1,365.22 | 494.42 (458.50–533.17) | 55.3 (50.1–60.0) |
| Leukemia/lymphoma, congenital and other immunodeficiencies, asplenia/hyposplenia | 8,515 | 508 | 1,888.59 | 268.98 (246.58–293.42) | 7,224 | 256 | 568.93 | 449.97 (398.09–508.61) | 52.2 (43.4–59.7) |
| HIV/AIDS | 2,648 | 152 | 536.35 | 283.40 (241.74–332.23) | 2,140 | 78 | 171.4 | 455.07 (364.50–568.15) | 57.3 (42.1–68.6) |
| Hematopoietic stem cell transplant/organ transplant | 2,220 | 234 | 615.53 | 380.16 (334.44–432.13) | 1,300 | 70 | 100.53 | 696.32 (550.90–880.13) | 45.1 (23.7–60.5) |
| HSCTb | 612 | 34 | 149.11 | 228.02 (162.92–319.12) | 417 | 10 | 31.66 | 315.82 (169.93–586.97) | 6.4 (-51.6–57.6)c |
| SOTb | 1611 | 201 | 467.36 | 430.08 (374.55–493.84) | 884 | 60 | 68.87 | 871.23 (676.46–1122.08) | 50.8 (29.1–65.9) |
Relative vaccine effectiveness (%) was calculated as (1 – hazard ratio) × 100 when the hazard ratio was ≤1; relative vaccine effectiveness (%) was calculated as ([1/hazard ratio] – 1) × 100 when the hazard ratio was >1.
Abbreviation. HSCT, hematopoietic stem cell transplant; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOT, solid organ transplant.
Adjusted for covariates age, sex, race/ethnicity, index date (in months), time between second dose and index date, number of outpatient and virtual visits, preventive care, Charlson comorbidity score, and immunocompromising sub-conditions, unless otherwise indicated.
Includes 4 individuals who received both SOT and HSCT.
HIV status removed from adjustment set due to lack of model convergence.
Table 4.
Incidence rate and relative vaccine effectiveness of the mRNA-1273 3-dose primary series in preventing SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death by month after index date among immunocompromised population, with 2-dose vaccinated comparison.
| Outcomes |
3-dose primary series vaccinated |
2-dose vaccinated |
Adjustedarelative Vaccine Effectiveness % (95 % CI) |
||||||
|---|---|---|---|---|---|---|---|---|---|
| N | Number of cases | Number of person-years | Incidence per 1000 person-years (95 % CI) | N | Number of cases | Number of person-years | Incidence per 1000 person-years (95 % CI) | ||
| SARS-CoV-2 infection | |||||||||
| 0 - <3 months | 21,942 | 881 | 4,003.68 | 220.05 (205.99–235.07) | 21,942 | 885 | 1,936.14 | 457.09 (427.95–488.22) | 57.2 (52.8–61.2) |
| 3 - <6 months | 6,195 | 412 | 649.95 | 633.89 (575.54–698.15) | 994 | 79 | 76.89 | 1,027.43 (824.11–1280.91) | 40.2 (21.6–54.4) |
| COVID-19 hospitalization | |||||||||
| 0 - <3 months | 21,942 | 33 | 4,049.92 | 8.15 (5.79–11.46) | 21,942 | 85 | 1,986.95 | 42.78 (34.59–52.91) | 86.1 (78.6–90.9) |
| 3 - <6 months | 6,301 | 43 | 678.02 | 63.42 (47.03–85.51) | 1,035 | 3 | 83.57 | 35.90 (11.58–111.30) | 44.5 (-48.7–84.2)b |
| COVID-19 hospital death | |||||||||
| 0 - <3 months | 21,942 | 2 | 4,051.82 | 0.49 (0.12–1.97) | 21,942 | 6 | 1,992.36 | 3.01 (1.35–6.70) | 87.1 (30.6–97.6)c |
Relative vaccine effectiveness (%) was calculated as (1 – hazard ratio) × 100 when the hazard ratio was ≤1; relative vaccine effectiveness (%) was calculated as ([1/hazard ratio] – 1) × 100 when the hazard ratio was >1.
Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Adjusted for covariates age, sex, race/ethnicity, index date (in months), time between second dose and index date, number of outpatient and virtual visits, preventive care, Charlson comorbidity score, and immunocompromising sub-conditions.
Adjusted for covariates age, sex, index date (in months), preventive care, Charlson comorbidity score, and immunocompromising sub-conditions.
Adjusted for covariates age, sex, index date (in months), time between second dose and index date, and immunocompromising sub-conditions (except HIV/AIDS).
4. Discussion
Our study provides important real-world evidence for significant protection of the mRNA-1273 3-dose primary series against SARS-CoV-2 infection, COVID-19 hospitalization, and death during COVID-19 hospitalization compared to 2 doses of mRNA-1273 in immunocompromised individuals; these findings were consistent across subgroups of demographic and clinical characteristics as well as immunocompromising conditions. Our results support recommendations for the third primary series dose of mRNA-1273 vaccine for additional protection of moderate to severely immunocompromised persons against severe COVID-19 outcomes [10]. Further, our study showed higher point estimates of the 3-dose vs 2-dose rVE against SARS-CoV-2 infection and COVID-19 hospitalization in the first 3 months compared to 3–6 months after the third dose, which is consistent with recommendations for a booster (fourth) dose for immunocompromised populations 3 months after 3-dose primary series [10].
While studies have shown immune responses in some immunocompromised individuals after 2 doses of an mRNA vaccine [21], others have reported immune responses in substantially fewer individuals with immune deficiency after 2 doses compared with healthy individuals [22]. Earlier immunogenicity studies reported lower seroconversion rates after COVID-19 vaccination in immunocompromised patients, compared to immunocompetent individuals [11]. Further, other immunogenicity studies have shown that patients who failed to achieve seroconversion after 2 doses of mRNA vaccine responded to the third dose. Studies utilizing EHR to evaluate VE suggested that 2 doses of mRNA vaccines were effective in preventing COVID-19 hospitalizations among US adults, but VE was lower in the immunocompromised population compared to the immunocompetent population [23], [24]. Studies have also reported a significantly higher VE of 3 doses than 2 doses in immunocompromised individuals including SOT recipients against COVID-19-associated hospitalization [12], [13]. In addition, we observed that the third dose also conferred additional protection against SARS-CoV-2 infection in those with a history of SARS-CoV-2 infection. This observation is consistent with previous reports of heightened immunologic responses to vaccination in previously infected individuals through hybrid of natural and vaccine immunity [25], [26].
There are several possible immunologic explanations for the reduced immune response and VE in immunocompromised individuals compared to immunocompetent individuals. T-cells have an important role in long-term protection conferred by immune memory; examples include CD8+ cytotoxic T-lymphocytes impeding virus replication, immune-stimulating cytokines, and CD4+ T-helper cells eliciting a multiplicity of functions that are critical for coordination of antiviral immunity [22]. Immunocompromised individuals, particularly those with combined defects of B- and T-cell immunity after transplantation and intensive chemotherapy [27], [28], [29], are at high risk of developing severe COVID-19 disease outcomes [30], [31], [32]. Studies have shown an association between B-cell depletion and low CD4+ T-cell counts, and increased COVID-19 disease severity [33], [34], [35]. In addition, vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells from germinal center reactions [36], [37]. A recent study reported on disrupted formation of neutralizing antibody-producing germinal centers and T follicular helper cells in individuals with compromised immune systems, which may help explain the hindered immune response in this population. Finally, both allogeneic HSCT and anti-CD20 therapy have been associated with increased duration of viral shedding and COVID-19 relapses, which are linked to virus replication and mutation [38], [39]. Further, although early administration of COVID-19 monoclonal antibody (mAb) treatment can improve COVID-19 outcomes of immunosuppressed individuals infected with SARS-CoV-2 [21], mAb can also lead to selection of mAb resistant variants [40]. As such, COVID-19 vaccines remain critical to provide adequate protection for these populations.
Our study has several notable strengths. First, we conducted a large, population-based, real-world study in an integrated health care system with a large, diverse, and stable population. KPSC’s comprehensive EHR enabled accurate capture of COVID-19 vaccine exposures, COVID-19 outcomes, and other demographic/clinical covariates. The matched cohort design increased generalizability to the immunocompromised adult population. We also reported rVE of the primary 3-dose series with 2 doses as the comparator as opposed to unvaccinated individuals, allowing us to estimate the added protection of the third dose relative to the second dose, and to reduce selection bias. While previous studies reported 3-dose vs 2-dose rVE of any mRNA vaccines combined (BNT162b2 or mRNA-1273) [12], [13], our study provided mRNA-1273-specific rVE estimates. Additionally, individuals with moderate-to-severe immunosuppression are not a homogeneous group with regards to VE, and severity of the immunocompromising condition could have an impact on VE. Indeed, VE (3 or 2-dose vaccinated vs unvaccinated) has been reported to vary considerably among specific immunocompromising subgroups [21], [22], [23], [41], [42], with lower VE linked to more severe immunosuppression compared to less severe immunosuppression [12], [22]. In our work, the rVE of 3 doses vs 2 doses was consistent across subgroups of immunocompromising conditions. We also controlled for subgroups of immunocompromising conditions in our multivariable analyses, which likely minimized potential confounding by severity of immunocompromising conditions. Further, while most existing data report rVE against COVID-19 hospitalization only, our study also assessed rVE against SARS-CoV-2 infection and COVID-19 hospital death as primary outcomes. Lastly, because our study period included follow-up through January 2022, our study included more relevant data since the predominance of the Omicron variant.
Nonetheless, our study has several limitations. First, due to the observational study design, there may be residual confounding from factors that are associated with both COVID-19 vaccination and the risk of COVID-19 (e.g., individual behaviors potentially impacting the care-seeking behavior and risk of COVID-19). However, because we compared 3-dose recipients with 2-dose recipients instead of unvaccinated individuals, we expect such unmeasured confounding to be minimal. Second, misclassification of SARS-CoV-2 infection may have occurred due to false positive or false negative test results or erroneous diagnosis codes recorded from claims; however, we expected this misclassification to be non-differential. Vaccine exposure misclassification was unlikely given the comprehensiveness and accuracy of our vaccination data from within and outside of KSPC. Third, we did not evaluate rVE associated with specific variants in this study. Delta and Omicron were the predominant SARS-CoV-2 variants during our observation period (August 2021 through January 2022) [17], with Delta being the dominant variant in the beginning and Omicron surpassing Delta in December 2021 [15]. VE against infection with these variants, Omicron in particular, has been reported to be lower than for other variants that circulated earlier in the pandemic [15]. Indeed, we observed that the rVE estimated for 3–6 months following the third dose, spanning the Omicron period, was lower than the first 3 months, spanning the Delta period. In addition, we adjusted for the month of the index date in rVE analyses by time after index date to account for varying infection rates of different dominant variants circulating during different calendar periods. Lower neutralizing efficiency of mRNA vaccines has been reported after infection with the Delta and Omicron variants compared to early strains of the virus [43]. Nevertheless, studies have demonstrated that receipt of a third dose of mRNA vaccine was highly effective at preventing COVID-19 hospitalization associated with Delta and Omicron [15]. Furthermore, immunocompromised populations may not mount an adequate immune response to the mRNA vaccines and thus remain at a higher risk of acquiring infections than the general population [10]. In fact, although mortality may be low in immunocompromised individuals infected with Omicron, morbidity remains a concern for this population [44]. Additionally, our ability to evaluate rVE in subgroups of immunocompromising conditions was limited due to the small number of individuals in some groups. For example, the point estimate for the rVE against SARS-CoV-2 infection for HSCT recipients was only 6.4 %, with a wide 95 % CI due to the limited sample size. Lastly, while a 100 µg mRNA-1273 dose was recommended as the third primary series dose for immunocompromised adults [45], some immunocompromised individuals in our study may have received the 50 µg mRNA-1273 dose as their third dose. We had dose data available for the 3-dose recipients who were vaccinated within the KPSC system (n = 17,261; 79 %). Among those with dose data available, 100 % received 100 µg doses in August and September 2021 before the 50 µg monovalent booster dose was authorized for broader adult populations in October 2021; 50 %, 25 %, and 24 % received 100 µg doses in October, November, and December 2021, respectively. Nevertheless, our results reflect real-world data on third doses administered to immunocompromised individuals.
In conclusion, the mRNA-1273 3-dose primary series was associated with a significantly higher rVE than 2 doses for immunocompromised individuals, and these results were consistent across subgroups of demographic/clinical characteristics and immunocompromising conditions. However, the higher rVE of the 3-dose vaccination series did not persist long-term for this population. These findings underscore the importance of immunocompromised patients completing the 3-dose primary series and support recommendations for a booster (fourth) dose for additional protection against SARS-CoV-2 infection and severe COVID-19 outcomes, particularly when variants that can evade vaccine-induced and natural immunity against earlier variants, such as Omicron and its subvariants, are dominant. Long-term follow-up is needed to fully evaluate VE and durability of protection of the 3-dose primary series of mRNA-1273 against COVID-19 outcomes in immunocompromised individuals.
5. Abstract presentation
Data from this work were partially presented in an oral presentation at IDWeek, Washington DC, in October 2022.
All authors attest they meet the ICMJE criteria for authorship.
Funding
This work was supported by Moderna, Inc.
CRediT authorship contribution statement
Jennifer H. Ku: Conceptualization, Methodology, Writing – original draft , Writing – review & editing . Lina S. Sy: Conceptualization, Methodology, Project administration, Writing – review & editing. Lei Qian: Conceptualization, Methodology, Formal analysis , Writing – review & editing. Bradley K. Ackerson: Methodology, Conceptualization, Writing – review & editing. Yi Luo: Methodology, Formal analysis, Writing – review & editing. Julia E. Tubert: Methodologym, Formal analysis, Writing – review & editing. Gina S. Lee: Methodology, Project administration, Writing – review & editing. Ana Florea: Conceptualization, Methodology, Writing – review & editing. Katia J. Bruxvoort: Conceptualization, Methodology, Writing – review & editing. Carla A. Talarico: Conceptualization, Methodology, Project administration, Supervision, Funding acquisition, Writing – review & editing. Sijia Qiu: Methodology, Formal analysis, Writing – review & editing. Yun Tian: Methodology, Formal analysis, Writing – review & editing. Hung Fu Tseng: Conceptualization, Methodology, Supervision, Funding acquisition, Writing – review & editing.
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JHK, LSS, LQ, BKA, YL, JET, GSL, AF, SQ, and HFT are employees of Kaiser Permanente Southern California, which has been contracted by Moderna to conduct this study. KJB is an adjunct investigator at Kaiser Permanente Southern California. YT was an employee of Kaiser Permanente Southern California at the time of preparing the manuscript. CAT was an employee of and a shareholder in Moderna Inc. at the time of these analyses; CAT is currently an employee of AstraZeneca. JHK received funding from GlaxoSmithKline unrelated to this manuscript. LSS received funding from GlaxoSmithKline and Dynavax unrelated to this manuscript. LQ received funding from GlaxoSmithKline and Dynavax unrelated to this manuscript. BKA received funding from GlaxoSmithKline, Dynavax, Genentech, and Pfizer unrelated to this manuscript. YL received funding from GlaxoSmithKline, and Pfizer unrelated to this manuscript. JET received funding from Pfizer unrelated to this manuscript. GSL received funding from GlaxoSmithKline unrelated to this manuscript. AF received funding from Pfizer, GlaxoSmithKline, and Gilead unrelated to this manuscript. KJB received funding from GlaxoSmithKline, Dynavax, Pfizer, and Gilead unrelated to this manuscript. SQ received funding from Dynavax unrelate.d to this manuscript. YT received funding from GlaxoSmithKline unrelated to this manuscript. HFT received funding from GlaxoSmithKline unrelated to this manuscript; HFT also served in advisory boards for Janssen and Pfizer.
Acknowledgments
Acknowledgments
This study was funded by Moderna, Inc. The authors would like to acknowledge the following Kaiser Permanente Southern California staff: Radha Bathala, Maria Navarro, Elsa Olvera, Joy Gelfond, Jonathan Arguello, Jeannie Song, and Anna Lawless for their contributions in manual chart review. The authors would also like to acknowledge the contributions by Moderna staff: Yamuna Paila, PhD, and Julie Vanas. Medical writing and editorial assistance were provided by Jared Mackenzie, PhD, of MEDiSTRAVA in accordance with Good Publication Practice (GPP3) guidelines, funded by Moderna, Inc., and under the direction of the authors. The authors thank the patients of Kaiser Permanente for their partnership with us to improve their health. Their information, collected through our electronic health record systems, leads to findings that help us improve care for our members and can be shared with the larger community.
IRB
The study was approved by the KPSC Institutional Review Board.
Data availability statement
The data presented in this study are not publicly available due to privacy concerns.
Informed consent statement
No informed consent was required as the use of electronic health records for this observational study involved minimal risk.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2023.04.075.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Data availability
The authors do not have permission to share data.
References
- 1.The World Health Organization. WHO Coronavirus (COVID-19) Dashboard; 2022.
- 2.Tesoriero J.M., Swain C.E., Pierce J.L., Zamboni L., Wu M., Holtgrave D.R., et al. COVID-19 outcomes among persons living with or without diagnosed HIV infection in New York State. JAMA Netw Open. 2021;4:e2037069. doi: 10.1001/jamanetworkopen.2020.37069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sharma A., Bhatt N.S., St Martin A., Abid M.B., Bloomquist J., Chemaly R.F., et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8:e185–e193. doi: 10.1016/S2352-3026(20)30429-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Negahdaripour M., Shafiekhani M., Moezzi S.M.I., Amiri S., Rasekh S., Bagheri A., et al. Administration of COVID-19 vaccines in immunocompromised patients. Int Immunopharmacol. 2021;99 doi: 10.1016/j.intimp.2021.108021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lombardi A., Butta G.M., Donnici L., Bozzi G., Oggioni M., Bono P., et al. Anti-spike antibodies and neutralising antibody activity in people living with HIV vaccinated with COVID-19 mRNA-1273 vaccine: a prospective single-centre cohort study. Lancet Reg Health Eur. 2022;13 doi: 10.1016/j.lanepe.2021.100287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Benotmane I., Gautier-Vargas G., Cognard N., Olagne J., Heibel F., Braun-Parvez L., et al. Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients. Kidney Int. 2021;99:1487–1489. doi: 10.1016/j.kint.2021.03.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kamar N., Abravanel F., Marion O., Couat C., Izopet J., Del Bello A. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385:661–662. doi: 10.1056/NEJMc2108861. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Mehrabi Nejad M.M., Shobeiri P., Dehghanbanadaki H., Tabary M., Aryannejad A., Haji Ghadery A., et al. Seroconversion following the first, second, and third dose of SARS-CoV-2 vaccines in immunocompromised population: a systematic review and meta-analysis. Virol J. 2022;19:132. doi: 10.1186/s12985-022-01858-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Mai A.S., Lee A., Tay R.Y.K., Shapiro L., Thakkar A., Halmos B., et al. Booster doses of COVID-19 vaccines for patients with haematological and solid cancer: a systematic review and individual patient data meta-analysis. Eur J Cancer. 2022;172:65–75. doi: 10.1016/j.ejca.2022.05.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Centers for Disease Control and Prevention. COVID-19 Vaccines for moderately or severely immunocompromised people; 2022.
- 11.Lee A.R.Y.B., Wong S.Y., Chai L.Y.A., Lee S.C., Lee M.X., Muthiah M.D., et al. Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis. BMJ. 2022;376:e068632. doi: 10.1136/bmj-2021-068632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kwon J.H., Tenforde M.W., Gaglani M., Talbot H.K., Ginde A.A., McNeal T., et al. mRNA Vaccine Effectiveness Against COVID-19 Hospitalization Among Solid Organ Transplant Recipients. J Infect Dis. 2022;226:797–807. doi: 10.1093/infdis/jiac118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Tenforde M.W., Patel M.M., Gaglani M., Ginde A.A., Douin D.J., Talbot H.K., et al. Effectiveness of a third dose of Pfizer-BioNTech and moderna vaccines in preventing COVID-19 hospitalization among immunocompetent and immunocompromised adults - United States, August-December 2021. MMWR Morb Mortal Wkly Rep. 2022;71:118–124. doi: 10.15585/mmwr.mm7104a2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Florea A., Sy L.S., Luo Y., Qian L., Bruxvoort K.J., Ackerson B.K., et al. Durability of mRNA-1273 against COVID-19 in the time of Delta: Interim results from an observational cohort study. PLoS One. 2022;17:e0267824. doi: 10.1371/journal.pone.0267824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Tseng H.F., Ackerson B.K., Luo Y., Sy L.S., Talarico C.A., Tian Y., et al. Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and Delta variants. Nat Med. 2022;28:1063–1071. doi: 10.1038/s41591-022-01753-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Koebnick C., Langer-Gould A.M., Gould M.K., Chao C.R., Iyer R.L., Smith N., et al. Sociodemographic characteristics of members of a large, integrated health care system: comparison with US Census Bureau data. Perm J. 2012;16:37–41. doi: 10.7812/tpp/12-031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Centers for Disease Control and Prevention. CDC COVID data tracker. Variant Proportions. Atlanta, GA: US Department of Health and Human Services; 2021.
- 18.Bruxvoort K.J., Sy L.S., Qian L., Ackerson B.K., Luo Y., Lee G.S., et al. Effectiveness of mRNA-1273 against delta, mu, and other emerging variants of SARS-CoV-2: test negative case-control study. BMJ. 2021;375:e068848. doi: 10.1136/bmj-2021-068848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Kim D.H., Schneeweiss S., Glynn R.J., Lipsitz L.A., Rockwood K., Avorn J. Measuring Frailty in Medicare Data: Development and Validation of a Claims-Based Frailty Index. J Gerontol A Biol Sci Med Sci. 2018;73:980–987. doi: 10.1093/gerona/glx229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Miettinen O.S. John Wiley & Sons. Print; New York: 1985. Theoretical Epidemiology: Principles of Occurrence Research in Medicine. [Google Scholar]
- 21.Baron F., Canti L., Ariën K.K., Kemlin D., Desombere I., Gerbaux M., et al. Insights From Early Clinical Trials Assessing Response to mRNA SARS-CoV-2 Vaccination in Immunocompromised Patients. Front Immunol. 2022;13 doi: 10.3389/fimmu.2022.827242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Oyaert M., De Scheerder M.A., Van Herrewege S., Laureys G., Van Assche S., Cambron M., et al. Evaluation of Humoral and Cellular Responses in SARS-CoV-2 mRNA Vaccinated Immunocompromised Patients. Front Immunol. 2022;13 doi: 10.3389/fimmu.2022.858399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Embi P.J., Levy M.E., Naleway A.L., Patel P., Gaglani M., Natarajan K., 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;70:1553–1559. doi: 10.15585/mmwr.mm7044e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Tenforde M.W., Patel M.M., Ginde A.A., Douin D.J., Talbot H.K., Casey J.D., et al. Effectiveness of Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccines for Preventing Coronavirus Disease 2019 Hospitalizations in the United States. Clin Infect Dis. 2022;74:1515–1524. doi: 10.1093/cid/ciab687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Abu-Raddad L.J., Chemaitelly H., Ayoub H.H., Yassine H.M., Benslimane F.M., Al Khatib H.A., et al. Association of Prior SARS-CoV-2 Infection With Risk of Breakthrough Infection Following mRNA Vaccination in Qatar. JAMA. 2021;326:1930–1939. doi: 10.1001/jama.2021.19623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hammerman A., Sergienko R., Friger M., Beckenstein T., Peretz A., Netzer D., et al. Effectiveness of the BNT162b2 Vaccine after Recovery from Covid-19. N Engl J Med. 2022;386:1221–1229. doi: 10.1056/NEJMoa2119497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Xhaard A., Xhaard C., D'Aveni M., Salvator H., Chabi M.L., Berceanu A., et al. Risk factors for a severe form of COVID-19 after allogeneic haematopoietic stem cell transplantation: a Société Francophone de Greffe de Moelle et de Thérapie cellulaire (SFGM-TC) multicentre cohort study. Br J Haematol. 2021;192:e121–e124. doi: 10.1111/bjh.17260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Lancman G., Mascarenhas J., Bar-Natan M. Severe COVID-19 virus reactivation following treatment for B cell acute lymphoblastic leukemia. J Hematology Oncol. 2020;13:131. doi: 10.1186/s13045-020-00968-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Mohan S., King K.L., Husain S.A., Schold J.D. COVID-19-associated mortality among kidney transplant recipients and candidates in the United States. Clin J Am Soc Nephrol. 2021;16:1695–1703. doi: 10.2215/CJN.02690221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.García-Suárez J., de la Cruz J., Cedillo Á., Llamas P., Duarte R., Jiménez-Yuste V., et al. Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: lessons from a large population-based registry study. J Hematology Oncol. 2020;13:133. doi: 10.1186/s13045-020-00970-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Heldman M.R., Kates O.S., Safa K., Kotton C.N., Georgia S.J., Steinbrink J.M., et al. Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic. Am J Transplant. 2022;22:279–288. doi: 10.1111/ajt.16840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Ponsford M.J., Ward T.J.C., Stoneham S.M., Dallimore C.M., Sham D., Osman K., et al. A systematic review and meta-analysis of inpatient mortality associated with nosocomial and community COVID-19 exposes the vulnerability of immunosuppressed adults. Front Immunol. 2021;12 doi: 10.3389/fimmu.2021.744696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Ambrosioni J., Blanco J.L., Reyes-Urueña J.M., Davies M.-A., Sued O., Marcos M.A., et al. Overview of SARS-CoV-2 infection in adults living with HIV. Lancet HIV. 2021;8:e294–e305. doi: 10.1016/S2352-3018(21)00070-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Calderón-Parra J., Múñez-Rubio E., Fernández-Cruz A., García-Sánchez M.C., Maderuelo-González E., López-Dosil M., et al. Incidence, clinical presentation, relapses and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients treated with anti-CD20 monoclonal Antibodies. Clin Infect Dis. 2022;74:1786–1794. doi: 10.1093/cid/ciab700. [DOI] [PubMed] [Google Scholar]
- 35.Duléry R., Lamure S., Delord M., Di Blasi R., Chauchet A., Hueso T., et al. Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy. Am J Hematol. 2021;96:934–944. doi: 10.1002/ajh.26209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Mesin L., Ersching J., Victora G.D. Germinal Center B Cell Dynamics. Immunity. 2016;45:471–482. doi: 10.1016/j.immuni.2016.09.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Lederer K, Bettini E, Parvathaneni K, Painter MM, Agarwal D, Lundgreen KA, et al. Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals. Cell. 2022;185:1008-24.e15. [DOI] [PMC free article] [PubMed]
- 38.Clark SA, Clark LE, Pan J, Coscia A, McKay LGA, Shankar S, et al. SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms. Cell. 2021;184:2605-17.e18. [DOI] [PMC free article] [PubMed]
- 39.Choi B., Choudhary M.C., Regan J., Sparks J.A., Padera R.F., Qiu X., et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med. 2020;383:2291–2293. doi: 10.1056/NEJMc2031364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Lohr B., Niemann D., Verheyen J. Bamlanivimab treatment leads to rapid selection of immune escape variant carrying the E484K mutation in a B.1.1.7-infected and immunosuppressed patient. Clin Infect Dis. 2021;73:2144–2145. doi: 10.1093/cid/ciab392. [DOI] [PubMed] [Google Scholar]
- 41.Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently authorized in the United States. Centers for Disease Control and Prevention; 2021.
- 42.Benotmane I., Gautier G., Perrin P., Olagne J., Cognard N., Fafi-Kremer S., et al. Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses. JAMA. 2021;326:1063–1065. doi: 10.1001/jama.2021.12339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Pérez-Then E., Lucas C., Monteiro V.S., Miric M., Brache V., Cochon L., et al. Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination. Nat Med. 2022;28:481–485. doi: 10.1038/s41591-022-01705-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Malahe S.R.K., Hoek R.A.S., Dalm V.A.S.H., Broers A.E.C., Den Hoed C.M., Manintveld O.C., et al. Clinical characteristics and outcomes of immunocompromised patients with coronavirus disease 2019 caused by the omicron variant: A prospective, observational study. Clin Infect Dis. 2022;76:e172–e178. doi: 10.1093/cid/ciac571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.United States Food and Drug Administration. Moderna COVID-19 vaccine health care provider fact sheet; 2022.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The authors do not have permission to share data.
The data presented in this study are not publicly available due to privacy concerns.