Baseline characteristics
Of the 6,964 included participants who reported accessing SARS-CoV-2 RT-PCR testing services at the participating study sites, 2579 participants reported a positive test. Of those 1,227 participants had complete information about vaccination, post-COVID symptoms and QoL. Of these, 276 individuals reported their symptoms less than 60 days following their positive PCR test and were therefore excluded from the study. The remaining 951 participants were included in the study. The baseline socio-demographic characteristics of the study participants are shown in Table 1. Overall, mean (SD) age was 46 (± 14·74) years old, 65·7% of participants were female, and 76·9% were of Jewish ethnicity, comparable to the 74% in the general population22. In terms of vaccination status 243 participants (25·6%) were unvaccinated, and 231 (24·3%), 227 (23·9%) and 250 (26·2%) received 1, 2 and 3 doses of COVID-19 vaccine respectively. Vaccinated participants were comparable with unvaccinated participants with respect to gender and marital status. The unvaccinated were more likely to be hospitalized for COVID-19 and slightly younger than those vaccinated (44·3 vs. 47·9 years, p < 0·001), likely reflecting the fact that vaccination in Israel was first available to older individuals. In the unvaccinated group, the mean duration between reporting testing positive for SARS-CoV-2 and answering the survey was 251 days compare to 401, 267 and 137 days for 1-dose, 2-doses, and 3-doses vaccinated, respectively (Table 1). The longer follow-up time for those who received one dose reflects the fact that the vast majority (206/231, 89·2%) of those who received a single dose were infected prior to vaccination, as the policy in Israel was initially for those infected to received single dose of vaccine. Of the 951 participants, 572 (60·1%) reported at least one post-COVID symptom and 547 (57.5%) one of the ten most common symptoms (listed in supplementary table 1). Of the 547 participants reporting symptoms, 298 had received 0 or 1 vaccine dose and 127 and 147 had received 2 and 3 doses respectively.
Table 1
Socio-demographic and clinical characteristics of participants
| Number of participants with available information | All participants | Unvaccinated | One Dose | Two Doses | Three Doses | p-value |
Variables | | 951 | 243 | 231 | 227 | 250 | |
Age (Mean (SD)) | 951 | 46·0 (14·7) | 44·6 (15·2) | 43·4 (12·8) | 48·3 (15·4) | 47·7 (15·0) | < 0·001 |
Age group (n,%) | 951 | | | | | | 0·002 |
> 60 | | 178 (18·7) | 45 (18·5) | 25 (10·8) | 53 (23·3) | 55 (22·0) | |
18–40 | | 387 (40·7) | 111 (45·7) | 106 (45·9) | 74 (32·6) | 96 (38·4) | |
41–60 | | 386 (40·6) | 87 (35·8) | 100 (43.3) | 100 (44.1) | 99 (39.6) | |
Sex (n,%) | 938 | | | | | | |
Male (%) | | 322 (34·3) | 88 (36·8) | 80 (35·1) | 76 (34·4) | 78 (31·2) | 0·614 |
Marital status (n,%) | 763 | | | | | | |
Single (%) | | 176 (23·1) | 48 (23·8) | 49 (26·2) | 40 (22·5) | 39 (19·9) | 0·525 |
Education (n,%) | 611 | | | | | | 0·070 |
Elementary school | | 71 (11·6) | 18 (12·7) | 24 (15·3) | 15 (10·1) | 14 (8·6) | |
High school | | 64 (10·5) | 25 (17·6) | 12 (7.6) | 15 (10·1) | 12 (7·4) | |
Postgraduate | | 162 (26·5) | 33 (23·2) | 40 (25·5) | 39 (26.2) | 50 (30·7) | |
Undergraduate | | 314 (51·4) | 66 (46·5) | 81 (51·6) | 80 (53·7) | 87 (53·4) | |
Ethnicity (n,%) | 762 | | | | | | |
Non-Jewish | | 247 (32·4) | 70 (34·7) | 90 (48·1) | 41 (23·0) | 46 (23.6) | < 0·001 |
Hospitalized (n,%) | 893 | | | | | | |
Yes | | 128 (14·3) | 47 (20·9) | 34 (16·8) | 30 (13·9) | 17 (6·8) | < 0·001 |
ICU admission (n,%) | 951 | | | | | | |
Yes | | 33 (28·0) | 17 (38·6) | 7 (22·6) | 6 (22·2) | 3 (18·8) | < 0·001 |
Diabetes (n,%) | 951 | | | | | | |
Yes | | 47 (4·9) | 5 (2·1) | 12 (5·2) | 15 (6·6) | 15 (6·0) | 0·099 |
Hypertension (n,%) | 951 | | | | | | |
Yes | | 100 (10·5) | 15 (6·2) | 19 (8·2) | 32 (14.1) | 34 (13·6) | 0·008 |
Asthma (n,%) | 951 | | | | | | |
Yes | | 34 (3·6) | 7 (2·9) | 7 (3·0) | 10 (4·4) | 10 (4·0) | 0·771 |
COPD (n,%) | 951 | | | | | | |
Yes | | 9 (0·9) | 2 (0·8) | 3 (1·3) | 2 (0·9) | 2 (0·8) | 0·938 |
Chronic kidney disease (n,%) | 951 | | | | | | |
Yes | | 6 (0·6) | 2 (0·8) | 0 (0·0) | 2 (0·9) | 2 (0·8) | 0·583 |
Days followed (Mean (SD)) | 951 | 261 (188) | 251 (171) | 401 (148) | 266 (189) | 137 (141 | < 0·001 |
Time since infection (n,%) | 951 | | | | | | < 0·001 |
3–6 months | | 443 (46·6) | 105 (43·2) | 13 (5·6) | 108 (47·6) | 217 (86·8) | |
7–12 months | | 234 (24·6) | 83 (34·2) | 89 (38·5) | 48 (21·1) | 14 (5·6) | |
>12 months | | 274 (28·8) | 55 (22·6) | 129 (55·8) | 71 (31·3) | 19 (7·6) | |
COPD: Chronic obstructive pulmonary disease, N: Number of participants responding per variable |
QoL and post-COVID symptoms
EQ-5D-5L dimensions
Compared with 2 and 3-dose vaccinated participants, a higher proportion of unvaccinated and one-dose vaccinated participants reported scores of 4 and 5 (indicating a lower QoL) in the mobility, pain, discomfort, and anxiety and depression dimensions of EQ-5D-5L (Fig. 1, supplementary Table 2). The proportion of individuals reporting no or only slight impairment in their usual activities was higher among those who received two or three doses compared with those who received 0 or 1 dose for the self-care, usual activities, and anxiety and depression dimensions (Fig. 1 and supplementary Table 2).
UI scores
Regardless of their COVID-19 vaccination status, participants not reporting post-acute COVID-19 symptoms had mean EQ-5D UI of 0·93 (SD = 0·20), compared to 0.84 (SD = 0.28) among individuals reporting at least one symptom 3–18 months post COVID. Overall, the mean EQ-5D UI was 0·82 (SD = 0·26) and 0·83 (SD = 0·25) among the double and triple vaccinated respectively, compared to 0·76 (SD = 0·33) and 0.78 (SD = 0·31) among those who had received 0 or 1 dose, respectively (Table 2). Among participants reporting at least one post-COVID symptom, those unvaccinated had a mean EQ-5D UI of 0·68 (SD = 0·40) compared with 0·74 (SD = 0·27) and 0·77 (SD = 0·27) for those doubly and triply vaccinated, respectively. In all age, gender, and ethnicity subgroups, the double and triple-vaccinated individuals reported higher mean UIs compared to the unvaccinated (Table 2). By time since infection those vaccinated reported higher unadjusted UIs compared to those unvaccinated (0-doses and 1-dose) at 3 to 6 months, (0·84 ± 0·24 vs. 0·76 ± 0·32, p = 0·019, Fig. 2). No overall significant difference in UI was found according to vaccination status among those reporting 7–12 months or more than 12 months after their acute SARS-CoV-2 infection.
Table 2
Crude mean utility indexes among participants according to baseline characteristics and vaccination status
| | Overall (vaccinated + unvaccinated at infection) | Stratified by number of vaccine doses received |
Variables | | n | Mean | SD | Covid vaccine doses | n | Mean | SD |
Age | 18–40 | 387 | 0·88 | 0·25 | 0-Doses | 111 | 0·82 | 0·33 |
1-Dose | 106 | 0·87 | 0·23 |
2-Doses | 74 | 0·92 | 0·19 |
3-Doses | 96 | 0·91 | 0·17 |
41–60 | 386 | 0·88 | 0·26 | 0-Doses | 87 | 0·84 | 0·34 |
1-Dose | 100 | 0·82 | 0·32 |
2-Doses | 100 | 0·94 | 0·14 |
3-Doses | 99 | 0·92 | 0·17 |
> 60 | 178 | 0·84 | 0·29 | 0-Doses | 45 | 0·77 | 0·33 |
1-Dose | 25 | 0·78 | 0.39 |
2-Doses | 53 | 0·86 | 0.26 |
3-Doses | 55 | 0·90 | 0·19 |
Sex | Female | 616 | 0·87 | 0·25 | 0-Doses | 151 | 0·85 | 0·28 |
1-Dose | 148 | 0·82 | 0·31 |
2-Doses | 145 | 0·90 | 0·21 |
3-Doses | 172 | 0·91 | 0·16 |
Male | 322 | 0·88 | 0·26 | 0-Doses | 88 | 0·80 | 0·37 |
1-Dose | 80 | 0·89 | 0·24 |
2-Doses | 78 | 0.92 | 0·20 |
3-Doses | 76 | 0·95 | 0·14 |
Ethnicity | Jewish | 515 | 0·88 | 0·25 | 0-Doses | 132 | 0·84 | 0·30 |
1-Dose | 97 | 0·82 | 0·32 |
2-Doses | 137 | 0·91 | 0·20 |
3-Doses | 149 | 0·91 | 0·16 |
Others | 247 | 0·85 | 0·30 | 0-Doses | 70 | 0·78 | 0·38 |
1-Dose | 90 | 0·85 | 0·29 |
2-Doses | 41 | 0·93 | 0·16 |
3-Doses | 46 | 0·88 | 0·24 |
Post Covid symptoms | Asymptomatic | 379 | 0·93 | 0·20 | 0-Doses | 92 | 0·90 | 0·26 |
1-Dose | 84 | 0·93 | 0·19 |
2-Doses | 100 | 0·93 | 0·19 |
3-Doses | 103 | 0·94 | 0·17 |
Symptomatic | 572 | 0·84 | 0·28 | 0-Doses | 151 | 0·77 | 0·36 |
1-Dose | 147 | 0·79 | 0·32 |
2-Doses | 127 | 0·90 | 0·19 |
3-Doses | 147 | 0·90 | 0·18 |
Months since SARS-CoV-2 testing | 3 to 6 months | 234 | 0·80 | 0·29 | 0-Doses | 105 | 0·78 | 0·32 |
1-Dose | 13 | 0.63 | 0·27 |
2-Doses | 108 | 0·84 | 0·24 |
3-Doses | 217 | 0·85 | 0·24 |
7 to 12 months | 443 | 0·82 | 0·27 | 0-Doses | 83 | 0·76 | 0·35 |
1-Dose | 89 | 0·84 | 0·26 |
2-Doses | 48 | 0·83 | 0·20 |
3-Doses | 14 | 0·76 | 0·24 |
> 12 months | 274 | 0·76 | 0·34 | 0-Doses | 55 | 0·74 | 0·37 |
1-Dose | 129 | 0·76 | 0·34 |
2-Dose | 71 | 0·77 | 0·32 |
3-Doses | 19 | 0·73 | 0·35 |
Association between COVID-19 vaccine and EQ‑5D‑5L UI and patient characteristics
After adjusting for age, ethnicity, hypertension, hospitalization (as a proxy for severity), and duration since testing positive for SARS-CoV-2), SARS-CoV-2-infected individuals vaccinated with 2 or 3 doses reported 0·05 points increase in UI compared to those unvaccinated at the time of infection (95%CI = 0·01– 0·10, p = 0·024, Table 3). Compared with those not vaccinated at the time of infection, the double-vaccinated reported an overall increase of 0·06 points in mean QoL score post-infection (95%CI = 0·004–0·11, p = 0·036, Table 3), but the change in those triply-vaccinated was not significant (+ 0·05, 95%CI= -0·01–0·10, p = 0·096, Table 3). When hospitalization was removed from the model, we found that vaccination was associated with a 0.06 point (p = 0·011) increase in UI among those vaccinated with two doses or more compared to those not (supplementary table s3).
Table 3
Crude and adjusted changes in utility indices for SARS-CoV-2 infected participants (all participants and for participants experiencing post-COVID symptoms, 3–18 months)
Variables | Variables | All participants | Participants experiencing post-covid symptoms |
n | Crude analysis | Adjusted | n | Crude analysis | Adjusted analysis |
| | | Change in utility score (percentage points) | 95% CI | P | Change in utility score (percentage points) | 95% CI | P | | Change in utility score (percentage points) | 95% CI | P | Change in utility score (percentage points) | 95% CI | P |
Sex | Male | 322 | Baseline | | | | | | 410 | | | | | | |
Female | 616 | 0·02 | -0·06–0·02 | 0.396 | -0·08 | -0.13 – -0·04 | < 0·001 | 154 | 0·04 | -0·02–0·10 | 0·147 | -0·06 | -0·13–0·01 | 0·071 |
Age (continuous) | | | <-0·01 | <-0·01– <-0·01 | < 0.001 | <-0·01 | <-0·01– <0·01 | 0·059 | 572 | < 0·01 | -0·01 – <0·01 | < 0·001 | <-0·01 | <-0·01– <0.01 | 0·106 |
Ethnicity | Jewish | 515 | Baseline | | | | | | 318 | | | | | | |
Other | 247 | -0·07 | -0·11 – -0·02 | 0·004 | -0·05 | -0·10 – <0·01 | 0·032 | 165 | -0·09 | -0·15 – -0·03 | 0·004 | -0·06 | -0·12 – -0·01 | 0·048 |
Vaccine doses | Unvaccinated at infection | 474 | Baseline | | | | | | 298 | | | | | | |
2 Doses | 227 | 0·05 | <-0·01– 0·09 | 0·060 | 0·06 | < 0·01–0·11 | 0·036 | 147 | 0·06 | -0·01–0·13 | 0·069 | 0·07 | <-0·01– 0·15 | 0·065 |
3 Doses | 250 | 0·06 | 0·01–0·10 | 0·011 | 0·05 | -0·01–0·10 | 0·096 | 127 | 0·09 | 0·03–0·15 | 0·006 | 0·09 | 0·02–0·16 | 0·024 |
2 + 3 Doses | 477 | 0·05 | 0·01–0·09 | 0·007 | 0·05 | 0·01–0·10 | 0·024 | 274 | 0·08 | 0·02–0·13 | 0·005 | 0·08 | 0·02–0·14 | 0·013 |
Days since SARS-CoV-2 positive (continuous) | | 951 | < 0·01 | <-0·01– <0·01 | 0·830 | < 0·01 | <-0·01– <0·01 | 0·828 | 572 | < 0·01 | <-0·01– <0·01 | 0·164 | < 0·01 | <-0·01– <0·01 | 0·914 |
Hypertension | No | 851 | Baseline | | | | | | 511 | | | | | | |
Yes | 100 | -0·16 | -0·22 – -0·10 | < 0·001 | -0·13 | -0·21 – -0·06 | < 0·001 | 61 | -0·17 | -0·26 – -0·09 | < 0·001 | -0·10 | -0·20 – -0·01 | 0·032 |
Hospitalisation (COVID-19 Severity) | No | 765 | Baseline | | | | | | 435 | | | | | | |
Yes | 128 | -0·25 | -0·30 – -0·19 | < 0·001 | -0·23 | -0·29 – -0·17 | < 0·001 | 95 | -0·29 | -0·35 – -0·22 | < 0·001 | -0·26 | -0.34 – -0·18 | < 0·001 |
When restricting the analysis to those experiencing ongoing post-COVID symptoms and after adjustment for potential confounders, participants who received two or three doses reported an increase of 0·08 in UI compared to those unvaccinated at the time of infection (CI = 0·02–0·14, p = 0·013). When stratifying by the number of doses received, the association was only statistically significant with three doses (+ 0·09, 95%CI = 0·02–0·16, p = 0·024, Table 3). When removing hospitalization out of the model, increases in UIs overall among the vaccinated compared to the unvaccinated at the time of infection were 0·08 (p = 0·012), 0·07 (p = 0·059) and 0·08 (p = 0·016) overall and for two and three or more doses respectively (supplementary table s3).
Association between COVID-19 vaccine and EQ‑5D‑5L UIs at different time points post-SARS-CoV-2 infection
Among participants who answered the survey between 3- and 6-months post-SARS-CoV-2 infection, before adjusting for confounders, those who received 2 or 3 doses of vaccine reported a 0·08-point increase in QoL (95%CI 0·03–0·14, p < 0·003). The effect size decreased, and the association was no longer statistically significant after adjusting for confounders significant in the univariate analysis (+ 0·03, 95%CI= -0·03–0·10, p = 0·303, Table 4). When adjusting for all confounders except hospitalization, vaccination was associated with a 0.07-point increase in EQ-5D-UI (p = 0·036, supplementary table s3). Conversely, when adjusting for hospitalization only, the association between vaccination and post-COVID QoL 3–6 months post-infection was not significant (+ 0·08 points, p = 0·303). Among those reporting 7–12 months post-infection, there was no overall association between COVID-19 vaccination and mean EQ‑5D‑5L UI, however among those reporting post-acute symptoms, double and triple vaccinated participants reported an increase of 0·15 in mean UI compared to those unvaccinated at the time of infection (95% CI 0·02–0·29, p = 0·024, Table 4). We did not detect any association between COVID-19 vaccination and mean EQ‑5D‑5L UI among participants reporting beyond 12 months post-SARS-CoV-2 infection, whether taking acute disease severity into account or not (Table 4).
Table 4
Crude and adjusted changes in utility indices for SARS-CoV-2 infected participants for all participants and for participants experiencing post-COVID symptoms, by time elapsed since testing
Time elapsed since testing | Variables | All participants | Participants experiencing post-covid symptoms |
n | Univariate model | Adjusted | n | Crude analysis | Adjusted analysis |
| Vaccine doses | | Change in utility score | 95% CI | P | Change in utility score | 95% CI | P | | Change in utility score | 95% CI | P | Change in utility score | 95% CI | P |
3–6 months | Unvaccinated at the time of infection | 118 | Baseline | | | | | | 80 | Baseline | | | | | |
2-Doses | 108 | 0·08 | 0·02–0.18 | 0·017 | 0·04 | -0·04–0·12 | 0·302 | 53 | 0·06 | -0·05–0·16 | 0·274 | -0·01 | -0·13–0·10 | 0.831 |
3-Doses | 217 | 0·09 | 0·03–0.14 | 0·005 | 0·03 | -0·04–0·10 | 0·396 | 128 | 0·11 | 0·02–0·19 | 0·012 | 0·05 | -0·05–0·14 | 0.325 |
2 + 3 Doses | 325 | 0·08 | 0·03–0.14 | 0·003 | 0·03 | -0·03–0·10 | 0·303 | 181 | 0·09 | 0·01–0·17 | 0·021 | 0·03 | -0·06–0·12 | 0.506 |
7–12 months | Unvaccinated at the time of infection | 172 | Baseline | | | | | | 109 | Baseline | | | | | |
2-Doses | 48 | 0·03 | -0·06–0.12 | 0·540 | 0·11 | -0·01–0·22 | 0·063 | 35 | 0·10 | -0·03–0·23 | 0·123 | 0·17 | 0·03–0·31 | 0·017 |
3-Doses | 14 | -0·04 | -0·19–0.12 | 0·639 | 0·06 | -0·12–0·24 | 0·529 | 9 | -0·01 | -0·22– 0·21 | 0·963 | 0·06 | -0·17–0·30 | 0·593 |
2 + 3 Doses | 62 | 0·01 | -0.07–0.10 | 0·746 | 0·10 | -0·01–0·20 | 0·072 | 44 | 0·07 | -0·04–0·19 | 0·187 | 0·15 | 0·02–0·29 | 0·024 |
> 12 months | Unvaccinated at the time of infection | 184 | Baseline | | | | | | 109 | Baseline | | | | | |
2-Doses | 71 | 0.01 | -0·08–0·11 | 0·765 | 0·06 | -0·06–0·17 | 0·348 | 39 | 0·04 | -0·09–0·17 | 0·505 | 0·05 | -0·07–0·16 | 0·410 |
3-Doses | 19 | -0.03 | -0·19–0.14 | 0·759 | 0·03 | -0·16–0·22 | 0·755 | 10 | 0·02 | -0·22–0·25 | 0·897 | 0·04 | -0·15–0·23 | 0·658 |
2 + 3 D0ses | 90 | 0.01 | -0·08–0·09 | 0·892 | 0·05 | -0·06–0·16 | 0·362 | 49 | 0·04 | -0·08–0·16 | 0·530 | 0·05 | -0·06–0·16 | 0·390 |
Adjusted for: ethnicity, sex, age, hypertension, and hospitalization |