Abstract
Objectives
To assess the variation of vaccine effectiveness against SARS-CoV-2 infection during the Delta wave according to frailty status among U.S. veterans.
Design
Test-negative case-control study of SARS-CoV-2 mRNA vaccine effectiveness.
Setting
Veterans Health Administration (VHA) medical centers.
Participants
Veterans 19 years and older who had at least one COVID-19/Flu like symptoms and received a SARS-CoV-2 PCR or antigen test at VHA medical centers between July 25 to September 30, 2021.
Intervention
mRNA vaccination.
Measurements
New SARS-CoV-2 infection. Vaccine effectiveness was defined as 1-odds of vaccination in cases/odds of vaccination in controls, where cases were patients who had a COVID-19 test and tested positive for SARS-CoV-2, and controls were those who tested negative. Frailty was measured using the VA frailty index, categorized as robust (0–<0.1), pre-frail (≥0.1–<0.21) and frail (≥0.21).
Results
A total of 58,604 patients (age:58.9±17.0, median:61, IQR:45–72; 87.5%men; 68.1%white; 1.3%African American, 8.3%Hispanic) were included in the study. Of these, 27,733 (47.3%) were robust, 16,276 (27.8%) were prefrail, and 14,595 (24.9%) were frail. mRNA vaccine effectiveness against the Delta variant symptomatic infection was lower in patients with frailty, 62.8 %(95%CI:59.8–65.7), versus prefrail 73.9%(95%CI:72.0–75.7), and robust, 77.0 %(95%CI:75.7–78.3).
Conclusions
This test-negative case control study showed that mRNA vaccine effectiveness against infection declined in veterans with frailty. Frailty status is a factor to consider when designing, developing, and evaluating COVID-19 vaccines.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s12603-023-1885-1 and is accessible for authorized users.
Key words: Frailty, COVID-19, SARS-CoV-2 Infection, vaccine effectiveness
Introduction
Older adults with acute COVID-19 infection are more likely to develop serious complications including hospitalizations and mortality (1,2). Although several effective and safe treatments have emerged since the onset of the pandemic, primary prevention with vaccination remains the mainstay for attenuating the negative effects of SARS-Cov-2 infection in older adults (3). Despite evidence suggesting lower vaccine effectiveness against the B.1.617.2-Delta variant, mRNA vaccines were still effective against the onset of infection (4,5). However, studies during the Delta wave demonstrated that older individuals had lower vaccine effectiveness and greater waning of protection than younger subjects (6). Even among older adults, vaccine effectiveness was not homogeneous, indicating that chronological age may not be the most appropriate marker of biological aging (7,8). Biological age may represent the heterogeneity of the aging process and serve as a better predictor of vaccine responses. Lower vaccine effectiveness may contribute to the higher rates of breakthrough infections which may subsequently lead to poor clinical outcomes seen in vulnerable older adults (4,9).
Frailty is characterized by diminished physiological reserve and susceptibility to a variety of stressors due to multiple organ system dysfunction (10). Frailty captures the high variability of aging and may therefore represent a better surrogate marker of biological age (11). Infections represent a major source of stress for older adults with frailty (12). Frailty is associated with a multitude of poor clinical outcomes and higher utilization in older adults with COVID-19 (13,14). Studies suggest that frailty negatively impacts responses to influenza and zoster vaccines in older individuals (15,16). Lower vaccine effectiveness may be explained in part by immunosenescence-an age-related decline of humoral and cellular immune responses, and inflammaging, a state of low-grade inflammation (17,18). A recent in vitro study showed that frailty is an independent predictor of impaired antibody responses to COVID-19 mRNA vaccines in older men (19). Our group also found reduced vaccine effectiveness against hospitalization and death after SARS-CoV-2 infection among patients with frailty in a cohort of veterans (20). Primary prevention is critical as SARS-CoV-2 infection is the first event in the multistep pathway leading to clinical complications (21). However, it is not clear whether vaccine protection against SARS-CoV-2 infection declines in patients with frailty.
The primary aim of our study was to compare vaccine effectiveness against COVID-19 infection according to frailty status. Secondary aims were to evaluate whether vaccine effectiveness waned over time; and, to compare the effectiveness of the two mRNA vaccines. Previous studies have shown that the Moderna vaccine, with its higher dose of mRNA content compared to the BNT162b2/Pfizer vaccine, may elicit a greater antibody response following vaccination (22), and may offer better protection against serious complications associated with the Delta variant (23). This study includes U.S. veterans receiving care at Veterans Health Administration (VHA) medical centers, who had at least one COVID-19/flu like symptom and were tested for SARS-CoV-2 during the Delta wave in the US (24). Our hypothesis was that vaccine effectiveness against infection during the Delta wave would be lower in patients with frailty.
Methods
Study Design, Data Sources and Study Population
We conducted a test-negative case-control study (4) to estimate vaccine effectiveness according to frailty status against SARS-CoV-2 infection caused by the Delta variant. Case participants were veterans 19 years and older who had a first-time positive polymerase-chain-reaction or antigen test for SARS-CoV-2 between July 25, 2021, and September 30, 2021 at Veterans Health Administration medical centers nationwide, and had at least one COVID-19/Flu like symptoms. Controls were defined as veterans who had at least one COVID-19/Flu like symptoms and at least one PCR or antigen-based test for SARS-CoV-2 at VHA from the same period but tested negative. We used VHA medical centers nationwide data from the VA COVID-19 Shared Data Resource (25). Comorbid conditions were captured using ICD-10 and Current Procedural Terminology (CPT) codes from the VA Corporate Data Warehouse outpatient and inpatient data domains. We excluded veterans who received vaccines other than mRNA vaccines; those missing information regarding vaccine type; those who received mixed type of vaccine, and those who were partially vaccinated at the time of testing, which is defined as people with only one dose or whose test was less than 7 days after dose 2. Veterans were considered fully vaccinated if they had received two vaccine doses more than 7 days prior to the time of testing. This study was approved by the Institutional Review Board at the Miami Veterans Affairs Healthcare System and was exempted from the requirement for informed consent.
Frailty
We operationalized frailty using a validated VA Frailty Index (VA-FI) which is based on the deficit accumulation conceptual framework (26). The VA-FI was generated using data elements two weeks before the SARS-CoV-2 testing to minimize changes in frailty status due to COVID-19 infection. The 31-item VA-FI was validated in over 2 million veterans (27), and includes variables from medical, psychological, functional, and social domains (Supplementary Appendix). This deficit accumulation framework does not rely on predetermined variables, is based on multimorbidity and disability, and is better suited to the veteran population (28). Each item was coded into binary values of 0 or 1, depending on the absence or presence of the deficit, respectively. The total index was calculated by adding up all values and dividing by 31 (29). We categorized patients according to the resulting scores into robust (0–<0.1), pre-frail (≥0.1–<0.21) and frail (≥0.21) (28).
Covariates
Covariates included age at the time of infection, body mass index (BMI), race, ethnicity, gender, smoking, and rurality (rural/small town, city town, or urban).
Symptoms
We retrieved symptoms 30 days prior to the date of SARS-CoV-2 testing including abdominal pain, chills, cough, diarrhea, dyspnea, fatigue, fever, headache, loss of smell, loss of taste, myalgia, nausea, rhinorrhea, and sore throat. These symptoms were first derived using ICD-10 codes, recorded vital signs, and then natural language processing tools for those symptoms not already captured by ICD-10 codes.
Statistical Analysis
We present continuous variables as means±standard deviation and medians with interquartile ranges, and categorical variables as frequencies and percentages. Multiple imputation by chained equations was used to impute the 1037 missing values of BMI using the MICE package in R. When information on race, ethnicity and smoking status was not available, we reported the data as “Unknown.” Conditional logistic regression was used to estimate vaccine effectiveness, adjusting for age, BMI, race, ethnicity, gender, smoking, and rurality. Vaccine effectiveness was defined as 1-odds of vaccination in cases/odds of vaccination in controls, where cases were patients who had at least one COVID-19/Flu like symptoms, had a COVID-19 test and tested positive for SARS-CoV-2, and controls were those who had at least one COVID-19/Flu like symptoms, had a COVID-19 test and tested negative for SARS-CoV-2. As patients with frailty tend to receive vaccinations earlier than the robust ones, we estimated vaccine effectiveness stratified by frailty status and periods after vaccination (0–1 months, 1–3 months, 3–5 months, and >5 months). Analyses were also stratified by age less than 65, 65–74, 75–84, and ≥85 years old. We also estimated vaccine effectiveness against symptomatic infection according to frailty status for the two mRNA vaccines. We performed statistical analysis with R (the R project for statistical computing, version 4.0.5).
Results
Patient Characteristics
We identified 136,493 veterans with a COVID-19 test at VHA medical centers nationwide between July 25 and September 30, 2021. After excluding 1,121 patients receiving an unknown vaccine type or the AstraZeneca vaccine; 7,672 who received the Janssen vaccine; 291 partially vaccinated patients; 165 patients who received mixed vaccination types; and 68,640 patients who did not have any COVID-19/Flu like symptoms, 58,604 patients were included in the final cohort. The final cohort consisted of 27,733(47.3%) robust, 16,276(27.8%) prefrail, and 14,595(24.9%) individuals with frailty. Table 1 shows the baseline characteristics of these patients according to frailty status. Patients with frailty were more likely to be older, male, have dyspnea, and be vaccinated. Among the 31,106 patients who were fully vaccinated, 15,510(49.9%) received Moderna and 15,596(50.1%) the Pfizer vaccines. Among the robust, a slightly higher number received the Pfizer vaccine (5,763,52.5%) compared to Moderna (5,113,47.5%). Among the patients with frailty (n=10,566), a slightly higher number received Moderna (5,439,51.5%) than the Pfizer vaccine (5,098,48.5%).
Table 1.
Baseline Characteristics According to Frailty Status
| Total n=58604 | Robust n = 27733 (47.3%) | Pre-Frail n = 16276 (27.8%) | Frail n = 14595 (24.9%) | |
|---|---|---|---|---|
| Age, mean (years) ±SD (median; IQR) | 58.9±17·0 (61; 45–72) | 50.6±16.3 (50; 36–64) | 62.4±14.6 (65; 53–73) | 70.8±11.5 (72; 64–77) |
| Age Groups, n (%) | ||||
| <65 | 33081 (56.4%) | 21318 (76.9%) | 8094 (49.7%) | 3669 (25.1%) |
| 65–74 | 15201 (25.9%) | 4338 (15.6%) | 5102 (31.3%) | 5761 (39.5%) |
| 75–84 | 7590 (13.0%) | 1659 (6.0%) | 2351 (14.4%) | 3580 (24.5%) |
| ≥85 | 2732 (4.7%) | 418 (1.5%) | 729 (4.5%) | 1585 (10.9%) |
| Male sex, n (%) | 51305 (87.5%) | 23648 (85.3%) | 14199 (87.2%) | 13458 (92.2%) |
| Race, n (%) | ||||
| White | 39953 (68.2%) | 18015 (65.0%) | 11186 (68.7%) | 10752 (73.7%) |
| Black | 12451 (21.2%) | 6048 (21.8%) | 3607 (22.2%) | 2796 (19.2%) |
| Asian | 601 (1.0%) | 398 (1.4%) | 148 (0.9%) | 55 (0.4%) |
| American Indian or Alaska Natives | 502 (0.9%) | 259 (0.9%) | 143 (0.9%) | 100 (0.7%) |
| Native Hawaiian or Other Pacific Islander | 543 (0.9%) | 285 (1.0%) | 145 (0.9%) | 113 (0.8%) |
| Unknown | 4554 (7.8%) | 2728 (9.8%) | 1047 (6.4%) | 779 (5.3%) |
| Ethnicity, n (%) | ||||
| Hispanic | 4874 (8.3%) | 2658 (9.6%) | 1255 (7.7%) | 961 (6.6%) |
| Not Hispanic | 49936 (85.2%) | 22430 (80.9%) | 14319 (88.0%) | 13187 (90.4%) |
| Unknown | 3794 (6.5%) | 2645 (9.5%) | 702 (4.3%) | 447 (3.1%) |
| BMIa, n (%) | ||||
| ≤20 | 2068 (3.5%) | 808 (2.9%) | 549 (3.4%) | 711 (4.9%) |
| 20–30 | 29376 (50.1%) | 14344 (51.7%) | 8011 (49.2%) | 7021 (48.1%) |
| 30–40 | 22207 (37.9%) | 10178 (36.7%) | 6412 (39.4%) | 5617 (38.5%) |
| >40 | 4953 (8.5%) | 2403 (8.7%) | 1304 (8.0%) | 1248 (8.5%) |
| Smoking, n (%) | ||||
| Current | 10183 (17.4%) | 4881 (17.6%) | 3008 (18.5%) | 2294 (15.7%) |
| Former Smoker | 21482 (36.7%) | 7926 (28.6%) | 6559 (40.3%) | 6997 (47.9%) |
| Never | 20437 (34.9%) | 9592 (34.6%) | 6012 (36.9%) | 4833 (33.1%) |
| Unknown | 6502 (11.1%) | 5334 (19.2%) | 697 (4.3%) | 471 (3.2%) |
| Rurality, n (%) | ||||
| City Town | 4388 (7.5%) | 1787 (6.4%) | 1322 (8.1%) | 1279 (8.8%) |
| Small Town/ Rural | 3435 (5.9%) | 1380 (5.0%) | 1089 (6.7%) | 966 (6.6%) |
| Urban | 44181 (75.4%) | 20913 (75.4%) | 12306 (75.6%) | 10962 (75.1%) |
| Unknown | 6600 (11.3%) | 3653 (13.2%) | 1559 (9.6%) | 1388 (9.5%) |
| Symptoms, n (%) | ||||
| Abdominal Pain | 5877 (10.0%) | 2653 (9.6%) | 1677 (10.3%) | 1547 (10.6%) |
| Chills | 12025 (20.5%) | 6511 (23.5%) | 3163 (19.4%) | 2351 (16.1%) |
| Cough | 30305 (51.7%) | 14687 (53.0%) | 8440 (51.9%) | 7178 (49.2%) |
| Diarrhea | 12985 (22.2%) | 6245 (22.5%) | 3585 (22.0%) | 3155 (21.6%) |
| Dyspnea | 20103 (34.3%) | 8176 (29.4%) | 5742 (35.3%) | 6185 (42.4%) |
| Fatigue | 20280 (34.6%) | 9357 (33.7%) | 5404 (33.2%) | 5519 (37.8%) |
| Fever | 20004 (34.1%) | 9863 (35.6%) | 5277 (32.4%) | 4864 (33.3%) |
| Headache | 16649 (28.4%) | 9118 (32.9%) | 4421 (27.2%) | 3110 (21.3%) |
| Loss of Smell | 1396 (2.4%) | 657 (2.4%) | 428 (2.6%) | 311 (2.1%) |
| Loss of Taste | 7058 (12.0%) | 3726 (13.4%) | 1917 (11.8%) | 1415 (9.7%) |
| Myalgia | 11712 (20.0%) | 6426 (23.2%) | 3070 (18.9%) | 2216 (15.2%) |
| Nausea | 13238 (22.6%) | 6433 (23.2%) | 3611 (22.2%) | 3194 (21.9%) |
| Rhinorrhea | 11707 (20.0%) | 6093 (22.0%) | 3284 (20.2%) | 2330 (16.0%) |
| Sore Throat | 12213 (20.8%) | 6779 (24.4%) | 3202 (19.7%) | 2232 (15.3%) |
| Average # of symptoms (median; IQR) | 3.3 ± 2.7 (2.0; 1.0–4.0) | 3.5 ± 2.7 (3.0; 1.0–5.0) | 3.3 ± 2·7 (2.0; 1.0–4.0) | 3.1 ± 2·7 (2.0; 1.0–4.0) |
| Fully Vaccinated, n(%) | 31106 (53.1%) | 10968 (39.4%) | 9737 (59.7%) | 10566 (72.3%) |
| Moderna mRNA-1273 | 15510 (26.5%) | 5113 (18.4%) | 4958 (30.5%) | 5439 (37.3%) |
| Pfizer/BNT162b2 | 15596 (26.6%) | 5763 (20.8%) | 4735 (29.1%) | 5098 (34.9%) |
a. BMI denotes body-mass index (the weight in kilograms divided by the square of the height in meters).
Vaccine Effectiveness according to Frailty Status and Age
As shown in Table 2, overall vaccine effectiveness for symptomatic infection was 71.8%(95%CI:70.7–72.8) but varied according to frailty status. Vaccine effectiveness was lower in patients with frailty at 62.8%(95%CI:59.8–65.7) as compared to pre-frail, 73.9%(95%CI:72.0–75.7), and robust 77.0%(95%CI:75.7–78.3). In terms of age, older patients had lower effectiveness for symptomatic infection, at 51.3%(95%CI:40.6–60.1) for patients ≥85, 61.5%(95%CI:56.9–65.6) for 75–84, 70.5%(95%CI:68.2–72.6) for 65–74 years compared to those younger than 65, 75.4%(95%CI:74.1–76.6). Regardless of age group, vaccine effectiveness was consistently lower in the frail compared to the prefrail and robust groups (Table 2).
Table 2.
Vaccine Effectiveness (%) for Infection According to Frailty Status and Age Groups
| All | Robust | Pre-frail | Frail | |
|---|---|---|---|---|
| All age | 71.8 (70.7–72.8) | 77.0 (75.7–78.3) | 73.9 (72.0–75.7) | 62.8 (59.8–65.7) |
| Age <65 | 75.4 (74.1–76.6) | 78.1 (76.6–79.6) | 75.9 (73.4–78.2) | 67.3 (62.4–71.7) |
| 65–74 | 70.5 (68.2–72.6) | 75.9 (72.3–79.0) | 76.2 (72.9–79.1) | 65.1 (60.5–69.2) |
| 75–84 | 61.5 (56.9–65.6) | 70.1 (62.8–76.8) | 66.8 (59.2–73.0) | 57.2 (49.3–64.0) |
| ≥85 | 51.3 (40.6–60.1) | 70.0 (49.5–82.4) | 53.4 (31.3–68.3) | 50.5 (34.7–62.4) |
Vaccine Effectiveness over Time according to Frailty Status
As shown in Table 3 and Figure 1, for 0–1 months, 1–3 months, 3–5 months, and >5 months after second dose of vaccination, patients with frailty demonstrated lower vaccine effectiveness for symptomatic infection. For the robust, vaccine effectiveness for symptomatic infection reached its peak within the first month of full vaccination, 90.8% (95%CI:86.6–94.0), whereas it was 82.7%(95%CI:73.4–89.2%) for the prefrail, and only 68.5%(95%CI:50.2–80.4) for patients with frailty during the same period. The peak of vaccine effectiveness occurred in the 1–3 months period for patients with frailty, at 75.5%(95%CI:69.1–80.7). In terms of waning over time, vaccine effectiveness declined to 57.3%(95%CI:53.6–60.8) for patients with frailty as compared with the prefrail 69.0%(95%CI:66.2–71.5) and robust 72.6%(95%CI:70.3–74.7), five or more months after vaccination.
Table 3.
Vaccine Effectiveness (%) for Infection According to Frailty Status and Time Intervals after Vaccination
| Robust | Pre-frail | Frail | |
|---|---|---|---|
| <1 month | 90.8 (86.6–94.0) | 82.7 (73.4–89.2) | 68.5 (50.2–80.4) |
| 1–3 months | 82.8 (79.7–85.5) | 85.6 (81.8–88.8) | 75.5 (69.1–80.7) |
| 3–5 months | 78.5 (76.7–80.0) | 77.6 (75.4–79.7) | 70.1 (66.9–73.0) |
| >5 months | 72.6 (70.3–74.7) | 69.0 (66.2–71.5) | 57.3 (53.6–60.8) |
Figure 1.
VE for symptomatic infection for 0–1, 1–3, 3–5, >5 time interval after fully vaccination
A: for both mRNA vaccines; B: for Moderna mRNA-1273 and Pfizer/BioNTech BNT162b2 vaccine separately.
Vaccine Effectiveness over Time according to Frailty Status and mRNA Vaccine Types
Patients with frailty demonstrated lower vaccine effectiveness with both mRNA vaccines (Table 4, Figure 1). Vaccine effectiveness for symptomatic infection was similar for the two vaccines within the first month of the vaccination among robust patients: Moderna, 91.9 %(95%CI:85.5–95.9); and Pfizer/BioNTech, 90.0 %(95%CI:83.8–94.2). In contrast, vaccine effectiveness within the first month of vaccination for patients with frailty was 80.0%(95%CI:57.1–91.5) for the Moderna vaccine, while only 60.7%(95%CI:29.2–78.6) for the Pfizer/BioNTech vaccine. For prefrail patients, the Moderna vaccine effectiveness was 89.1%(95%CI:75.9–95.9), higher than the Pfizer/BioNTech vaccine 78.7%(95%CI:64.6–87.7), but with overlapping confidence intervals. Furthermore, overall vaccine effectiveness for the Pfizer/BioNTech vaccine waned faster than Moderna: after 5-months, overall vaccine effectiveness was 71.8%(95%CI:70.1–73.5) for Moderna, vs. 57.0%(95%CI:54.5–59.3) for Pfizer/BioNTech (Table 4). In terms of frailty status, five or more months after full vaccination, vaccine effectiveness for symptomatic infection declined to 78.1%(95%CI:75.5–80.5) for Moderna, and to 67.5%(95%CI:64.1–70.6) for the Pfizer/BioNTech vaccine in the robust; declined to 74.8%(95%CI:71.9–77.4) for the Moderna, and to 62.4 %(95%CI:58.3–66.0) for the Pfizer/BioNTech vaccine in the prefrail; and to 66.7%(95%CI:63.2–69.9) for the Moderna, and to 45.6%(95%CI:40.0–50.7) for the Pfizer/BioNTech vaccine in the frail groups (Table 4, Figure 1).
Table 4.
Vaccine Effectiveness (%) for Infection According to Frailty Status and Time Intervals after Vaccination by Vaccine Type
| All | Robust | Pre-frail | Frail | |
|---|---|---|---|---|
| Moderna mRNA-1273 | ||||
| <1 month | 88.9 (83.4–92.8) | 91.9 (85.5–95.9) | 89.1 (75.9–95.9) | 80.0 (57.1–91.5) |
| 1–3 months | 86.6 (83.9–88.9) | 86.6 (82.7–89.8) | 89.8 (85.1–93.2) | 83.8 (77.2–88.7) |
| 3–5 months | 81.7 (80.4–83.0) | 84.0 (82.0–85.7) | 84.3 (82.1–86.2) | 77.0 (73.8–79.7) |
| >5 months | 71.8 (70.1–73.5) | 78.1 (75.5–80.5) | 74.8 (71.9–77.4) | 66.7 (63.2–69.9) |
| Pfizer/BioNTech BNT162b2 | ||||
| <1 month | 81.9 (75.8–86.7) | 90.0 (83.8–94.2) | 78.7 (64.6–87.7) | 60.7 (29.2–78.6) |
| 1–3 months | 76.9 (73.3–80.2) | 79.4 (74.7–83.4) | 81.5 (75.1–86.5) | 64.2 (51.3–73.9) |
| 3–5 months | 68.5 (66.4–70.4) | 73.2 (70.6–75.7) | 68.9 (65.0–72.4) | 60.2 (54.6–65.0) |
| >5 months | 57.0 (54.5–59.3) | 67.5 (64.1–70.6) | 62.4 (58.3–66.0) | 45.6 (40.0–50.7) |
Discussion
Using a test-negative case control study design, we investigated the effectiveness of mRNA vaccines against SARS-CoV-2 infection during the Delta surge in 2021 according to frailty status. We also estimated vaccine effectiveness at several periods after full vaccination. We observed differences in the peaks and waning patterns of vaccine effectiveness in patients with frailty compared with patients who were robust and prefrail. Consistent with our hypothesis, vaccine effectiveness against symptomatic infection was lower in patients with frailty compared to the robust and pre-frail groups. Furthermore, the peak of vaccine effectiveness against infection occurred later in patients with frailty. The waning of vaccine effectiveness was also more pronounced in patients with frailty compared to robust and prefrail. In terms of mRNA vaccine type, the Moderna mRNA-1273 vaccine showed higher vaccine effectiveness than the Pfizer/BioNTech BNT162b2 vaccine, and the difference in vaccine effectiveness between Moderna and Pfizer/BioNTech vaccine was even larger for patients with frailty. These results suggest that frailty is an important factor to be considered when monitoring mRNA vaccine effectiveness; and when developing vaccines and evaluating vaccine efficacy.
As we predicted, mRNA vaccine effectiveness against symptomatic COVID-19 infection was lower in patients with frailty compared to the robust and pre-frail groups. Furthermore, the peak of vaccine effectiveness against infection occurred later (1–3 month after full vaccination) in patients with frailty, compared to the robust (<1 month after fully vaccination). Our findings are consistent with previous studies revealing an independent association of frailty with reduced effectiveness and waning of protection against hospitalizations and all-cause mortality, downstream complications of SARS-CoV-2 infection (20). To the best of our knowledge, this is the first report of an association of frailty status with reduced mRNA vaccine effectiveness against infection during the Delta wave. These findings are important as SARS-CoV-2 infection is the initial insult that may elicit a chain of events leading to serious complications in vulnerable individuals living with frailty (12). Prevention of infection with vaccines then becomes a critical and cost-effective strategy to prevent infection and subsequent complications in this population (8,30). Although mRNA vaccines remain protective in individuals with frailty, the reduced effectiveness against infection in these individuals is concerning. Future prospective studies with other vaccine types, more diverse study samples or populations, and SARS-CoV-2 variants are needed to confirm that frailty is in fact a critical risk factor for reduced vaccine effectiveness against infection. Until these findings are confirmed, this evidence suggest that health care professionals must routinely assess their older patients for frailty using a variety of existing instruments (13). In addition to an aggressive vaccination approach, the prompt implementation of public health measures becomes an important primary prevention strategy that may encompass social distancing precautions, contact tracing and surveillance, and testing for those exposed individuals (31). Patients, caregivers, and health care professionals must also maintain a high index of suspicion for any atypical presentations that may indicate the onset of infection (32). Clinicians caring for patients with frailty should have a lower threshold for promptly initiating treatment for these patients with supportive treatments; antivirals, monoclonal antibodies, or both (33,34). In terms of improving vaccine immunogenicity, future research including participants with frailty, may investigate vaccine enhancing strategies including escalating antigen doses, more frequent boosters, use of adjuvants, use of recombinant agents or alternative vaccine types (35). This highlights the critical need to intentionally include participants across grades of frailty and explicitly include frailty in analysis plans in future vaccine studies including in earlier trial phases where doses and vaccine constituents are selected for their optimal immune and clinical responses. If the possibility that different doses or composition might benefit frail participants is not considered in product development phases, opportunities to optimize protection in this vulnerable group will be lost.
In terms of mRNA vaccine type, the Moderna mRNA-1273 vaccine showed higher overall effectiveness than the Pfizer/BioNTech BNT162b2 vaccine. Previous studies have shown the efficacy and effectiveness of the Moderna vaccine against the Delta variant (23) which is attributed to its larger mRNA content and longer interval between doses (36,37). Furthermore, when stratified according to frailty status, the Moderna vaccine had greater effectiveness against infection for all the periods compared to the Pfizer/BioNTech vaccine, except for <1 month time interval in the robust patients. Once again, these results are consistent with our previous report of the superior protection that the Moderna vaccine confers against hospitalization and mortality (20). These results again highlight a potential strategy for patients with frailty, that is increasing the amount of antigen, which may stimulate higher vaccine immunogenicity in these individuals (38). More studies are needed to confirm these findings. In the interim, clinicians should consider the use of the Moderna vaccine as a potentially better alternative for patients with frailty, and shorter intervals between booster doses for frail individuals could be an additional consideration.
Strengths of the study include its large population, capture of comprehensive medical information from electronic health record systems, accurate recording of vaccination status, timing and type, and determination of frailty status using a validated instrument, which allowed for estimation of vaccine effectiveness stratified by age, frailty status, and time interval from vaccination to infection. Limitations include that the test-negative case-control design is observational and therefore subject to potential bias (39). Although the test-negative design can help ensure cases and controls are similar in terms of exposure and health care seeking, there may be other unaccounted confounding factors. We used a frailty index based on the deficit accumulation framework. Further studies comparing the two main approaches of identifying frail patients (deficit accumulation model versus frailty phenotype model) in relation to COVID-19 vaccination effectiveness could help further clarify the role of frailty. Other limitations include our predominantly male population, which means these findings may not be generalizable to females. Also, it is not clear that these results can be generalized to other SARS-CoV-2 variants such as the Omicron. As our cohort consists of patients who were tested July 2021-September 2021, we did not include patients who received a booster shot, as VHA began administrating booster shots late September 2021.
Our results suggest that identifying persons with frailty receiving mRNA vaccination may allow clinicians to be more cognizant of the potentially subtle and atypical presentations of SARS-CoV2 in older adults with frailty (32), and to thoroughly evaluate and treat these patients. Therapeutic options may include the early use of antivirals (34) or monoclonal antibodies (33), interventions that will also deserve more formal study into the right combination of mitigating strategies. Although there is no clear evidence that support these recommendations specifically in patients with frailty, most of these patients may already meet existing criteria (40). These latter interventions will certainly deserve more formal study into their efficacy, effectiveness and safety and the right combination of strategies in patients with frailty. Whether older adults with frailty and asymptomatic infection would benefit is also unclear.
Conclusions
Overall, our study showed that in patients with frailty, vaccine effectiveness against infection was decreased; the peak of vaccine effectiveness against infection was delayed; and the waning of vaccine effectiveness was more pronounced. The Moderna mRNA-1273 vaccine showed higher vaccine effectiveness than the Pfizer/BioNTech BNT162b2 vaccine, and the difference in vaccine effectiveness between Moderna and Pfizer/BioNTech vaccine was even larger for patients with frailty. These results suggest that frailty is an important factor to be considered when developing future vaccines, and when evaluating vaccine efficacy and effectiveness on an ongoing basis.
Supplementary Appendix
Vaccine Effectiveness Against SARS-CoV-2 Infection According to Frailty Status among US Veterans
Author Contributions: Fei Tang: Study concept and design, acquisition of the data, analysis and interpretation of data, and preparation of the manuscript. Iriana S. Hammel: Study concept and design, literature review, and preparation of the manuscript. Melissa K Andrew: Study concept and design and preparation of the manuscript. Jorge G. Ruiz: Study concept and design, literature review, and preparation of the manuscript.
Funding sources: This material is the result of work supported with resources and the use of facilities at the Miami VA Healthcare System GRECC and at the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13–457.
Conflict of Interest: Jorge G. Ruiz holds a grant from Longeveron Inc and received consulting fee from Pfizer. Melissa K Andrew reports grants from the Canadian Frailty Network, CIHR, Public Health Agency of Canada, Sanofi, Pfizer, Merck and GSK, and payments from Pfizer, Sanofi and Seqirus outside the submitted work. Fei Tang and Iriana S. Hammel declare no competing interests.
Ethics declaration: A protocol of this study was submitted to and approved by the Miami VA Healthcare System Institutional Review Board (IRB) and was exempted from informed consent.
Footnotes
Sponsor’s Role: The work was supported by the Geriatric research, education, and clinical center (GRECC), Miami Veterans Affair. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; in the preparation of the manuscript; or the review or approval of the manuscript.
References
- 1.Garg S, Kim L, Whitaker M, et al. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458–464. doi: 10.15585/mmwr.mm6915e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bonanad C, Garcia-Blas S, Tarazona-Santabalbina F, et al. The Effect of Age on Mortality in Patients With COVID-19: A Meta-Analysis With 611,583 Subjects. J Am Med Dir Assoc. 2020;21(7):915–918. doi: 10.1016/j.jamda.2020.05.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Moline HL, Whitaker M, Deng L, et al. Effectiveness of COVID-19 Vaccines in Preventing Hospitalization Among Adults Aged >/=65 Years — COVID-NET, 13 States, February–April 2021. MMWR Morb Mortal Wkly Rep. 2021;70(32):1088–1093. doi: 10.15585/mmwr.mm7032e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bernal, J.L., Andrews, N., Gower, C., et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. Bmj-British Medical Journal 2021;373. doi:10.1136/bmj.n1088 [DOI] [PMC free article] [PubMed]
- 5.Pormohammad, A., Zarei, M., Ghorbani, S., et al. Effectiveness of COVID-19 Vaccines against Delta (B.1.617.2) Variant: A Systematic Review and Meta-Analysis of Clinical Studies. Vaccines (Basel) 2021;10(1). doi: 10.3390/vaccines10010023 [DOI] [PMC free article] [PubMed]
- 6.Andrews N, Tessier E, Stowe J, et al. Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines. New England Journal of Medicine. 2022;386(4):340–350. doi: 10.1056/NEJMoa2115481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Fulop T, McElhaney J, Pawelec G, et al. Frailty, Inflammation and Immunosenescence. Interdiscip Top Gerontol Geriatr. 2015;41:26–40. doi: 10.1159/000381134. [DOI] [PubMed] [Google Scholar]
- 8.Andrew MK, McElhaney JE. Age and frailty in COVID-19 vaccine development. Lancet. 2020;396(10267):1942–1944. doi: 10.1016/S0140-6736(20)32481-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Soiza RL, Scicluna C, Thomson EC. Efficacy and safety of COVID-19 vaccines in older people. Age and Ageing. 2021;50(2):279–283. doi: 10.1093/ageing/afaa274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–56. doi: 10.1093/gerona/56.3.M146. [DOI] [PubMed] [Google Scholar]
- 11.Mitnitski AB, Graham JE, Mogilner AJ, Rockwood K. Frailty, fitness and late-life mortality in relation to chronological and biological age. BMC Geriatr. 2002;2:1. doi: 10.1186/1471-2318-2-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Nidadavolu LS, Walston JD. Underlying Vulnerabilities to the Cytokine Storm and Adverse COVID-19 Outcomes in the Aging Immune System. J Gerontol A Biol Sci Med Sci. 2021;76(3):e13–e18. doi: 10.1093/gerona/glaa209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Dumitrascu F, Branje KE, Hladkowicz ES, Lalu M, McIsaac DI. Association of frailty with outcomes in individuals with COVID-19: A living review and metaanalysis. J Am Geriatr Soc. 2021;69(9):2419–2429. doi: 10.1111/jgs.17299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Pranata R, Henrina J, Lim MA, et al. Clinical frailty scale and mortality in COVID-19: A systematic review and dose-response meta-analysis. Arch Gerontol Geriatr. 2021;93:104324. doi: 10.1016/j.archger.2020.104324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Andrew MK, Shinde V, Ye L, et al. The Importance of Frailty in the Assessment of Influenza Vaccine Effectiveness Against Influenza-Related Hospitalization in Elderly People. Journal of Infectious Diseases. 2017;216(4):405–414. doi: 10.1093/infdis/jix282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Curran D, Him JH, Matthews S, et al. Recombinant Zoster Vaccine Is Efficacious and Safe in Frail Individuals. Journal of the American Geriatrics Society. 2021;69(3):744–752. doi: 10.1111/jgs.16917. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gruver AL, Hudson LL, Sennpowski GD. Immunosenescence of ageing. Journal of Pathology. 2007;211(2):144–156. doi: 10.1002/path.2104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Collerton J, Martin-Ruiz C, Davies K, et al. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: Cross-sectional findings from the Newcastle 85+ Study. Mechanisms of Ageing and Development. 2012;133(6):456–466. doi: 10.1016/j.mad.2012.05.005. [DOI] [PubMed] [Google Scholar]
- 19.Semelka, C.T., DeWitt, M.E., Callahan, K.E., et al. Frailty and COVID-19 mRNA Vaccine Antibody Response in The COVID-19 Community Research Partnership. The Journals of Gerontology: Series A 2022. doi: 10.1093/gerona/glac095 [DOI] [PMC free article] [PubMed]
- 20.Tang F, Hammel IS, Andrew MK, Ruiz JG. COVID-19 mRNA vaccine effectiveness against hospitalisation and death in veterans according to frailty status during the SARS-CoV-2 delta (B. 1.617. 2) variant surge in the USA: a retrospective cohort study. The Lancet Healthy Longevity. 2022;3(9):e589–98. doi: 10.1016/S2666-7568(22)00166-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Perrotta F, Corbi G, Mazzeo G, et al. COVID-19 and the elderly: insights into pathogenesis and clinical decision-making. Aging Clin Exp Res. 2020;32(8):1599–1608. doi: 10.1007/s40520-020-01631-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Naranbhai V, Garcia-Beltran WF, Chang CC, et al. Comparative Immunogenicity and Effectiveness of mRNA-1273, BNT162b2, and Ad26.COV2.S COVID-19 Vaccines. J Infect Dis. 2022;225(7):1141–1150. doi: 10.1093/infdis/jiab593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kow CS, Ramachandram DS, Hasan SS. The effectiveness of mRNA-1273 vaccine against COVID-19 caused by Delta variant: A systematic review and metaanalysis. J Med Virol. 2022;94(5):2269–2274. doi: 10.1002/jmv.27568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Del Rio C, Malani PN, Omer SB. Confronting the delta variant of SARS-CoV-2, summer 2021. JAMA. 2021;326(11):1001–1002. doi: 10.1001/jama.2021.14811. [DOI] [PubMed] [Google Scholar]
- 25.Dickerman BA, Gerlovin H, Madenci AL, et al. Comparative effectiveness of BNT162b2 and mRNA-1273 vaccines in US veterans. New England Journal of Medicine. 2022;386(2):105–115. doi: 10.1056/NEJMoa2115463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci. 2007;62(7):722–7. doi: 10.1093/gerona/62.7.722. [DOI] [PubMed] [Google Scholar]
- 27.Cheng D, DuMontier C, Yildrim C, et al. Updating and Validating the U.S. Veterans Affairs Frailty Index: Transitioning From ICD-9 to ICD-10 (vol 76, pg 1318, 2021) Journals of Gerontology Series a-Biological Sciences and Medical Sciences. 2022;77(2):E107–E107. doi: 10.1093/gerona/glab159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Orkaby AR, Nussbaum L, Ho Y-L, et al. The Burden of Frailty Among US Veterans and Its Association with Mortality, 2002–2012. Journals of Gerontology Series a-Biological Sciences and Medical Sciences. 2019;74(8):1257–1264. doi: 10.1093/gerona/gly232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Searle SD, Mitnitski A, Gahbauer E, Gill T M, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8:24. doi: 10.1186/1471-2318-8-24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Andrew MK, Searle SD, McElhaney JE, et al. COVID-19, frailty and long-term care: Implications for policy and practice. Journal of Infection in Developing Countries. 2020;14(5):428–432. doi: 10.3855/jidc.13003. [DOI] [PubMed] [Google Scholar]
- 31.Talic S, Shah S, Wild H, et al. Effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality: systematic review and meta-analysis. BMJ. 2021;375:e068302. doi: 10.1136/bmj-2021-068302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Tay HS, Harwood R. Atypical presentation of COVID-19 in a frail older person. Age Ageing. 2020;49(4):523–524. doi: 10.1093/ageing/afaa068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Libster R, Perez Marc G, Wappner D, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021;384(7):610–618. doi: 10.1056/NEJMoa2033700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Arbel R, Wolff Sagy Y, Hoshen M, et al. Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge. N Engl J Med. 2022;387(9):790–798. doi: 10.1056/NEJMoa2204919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Andrew MK, Bowles SK, Pawelec G, et al. Influenza Vaccination in Older Adults: Recent Innovations and Practical Applications. Drugs Aging. 2019;36(1):29–37. doi: 10.1007/s40266-018-0597-4. [DOI] [PubMed] [Google Scholar]
- 36.Self WH, Tenforde MW, Rhoads JP, et al. Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions — United States, March–August 2021. Mmwr-Morbidity and Mortality Weekly Report. 2021;70(38):1337–1343. doi: 10.15585/mmwr.mm7038e1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Bajema KL, Dahl RM, Prill MM, et al. Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalization — Five Veterans Affairs Medical Centers, United States, February 1–August 6, 2021. Mmwr-Morbidity and Mortality Weekly Report. 2021;70(37):1294–1299. doi: 10.15585/mmwr.mm7037e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Muller L, Andree M, Drexler I, et al. Age-dependent Immune Response to the Biontech/Pfizer BNT162b2 Coronavirus Disease 2019 Vaccination. Clin Infect Dis. 2021;73(11):2065–2072. doi: 10.1093/cid/ciab381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Dean NE, Hogan JW, Schnitzer ME. Covid-19 vaccine effectiveness and the test-negative design. New England Journal of Medicine. 2021;385(15):1431–3. doi: 10.1056/NEJMe2113151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2022 (COVID-19) Treatment Guidelines. 2022; Available at: https://www.covid19treatmentguidelines.nih.gov/about-the-guidelines/whats-new/. Accessed September 5, 2022.