Effectiveness of COVID-19 vaccines in a large European hemodialysis cohort

Background Hemodialysis patients have high-risk of severe SARS-CoV-2 infection but were unrepresented in randomized controlled trials evaluating the safety and efficacy of COVID-19 vaccines. We estimated the real-world effectiveness of COVID-19 vaccines in a large international cohort of hemodialysis patients. Methods In this historical, 1:1 matched cohort study, we included adult hemodialysis patients receiving treatment from December 1, 2020, to May 31, 2021. For each vaccinated patient, an unvaccinated control was selected among patients registered in the same country and attending a dialysis session around the first vaccination date. Matching was based on demographics, clinical characteristics, past COVID-19 infections and a risk score representing the local background risk of infection at vaccination dates. We estimated the effectiveness of mRNA and viral-carrier COVID-19 vaccines in preventing infection and mortality rates from a time-dependent Cox regression stratified by country. Results In the effectiveness analysis concerning mRNA vaccines, we observed 850 SARS-CoV-2 infections and 201 COVID-19 related deaths among the 28110 patients during a mean follow up of 44 ± 40 days. In the effectiveness analysis concerning viral-carrier vaccines, we observed 297 SARS-CoV-2 infections and 64 COVID-19 related deaths among 12888 patients during a mean follow up of 48 ± 32 days. We observed 18.5/100-patient-year and 8.5/100-patient-year fewer infections and 5.4/100-patient-year and 5.2/100-patient-year fewer COVID-19 related deaths among patients vaccinated with mRNA and viral-carrier vaccines respectively, compared to matched unvaccinated controls. Estimated vaccine effectiveness at days 15, 30, 60 and 90 after the first dose of a mRNA vaccine was: for infection, 41.3%, 54.5%, 72.6% and 83.5% and, for death, 33.1%, 55.4%, 80.1% and 91.2%. Estimated vaccine effectiveness after the first dose of a viral-carrier vaccine was: for infection, 38.3% without increasing over time and, for death, 56.6%, 75.3%, 92.0% and 97.4%. Conclusion In this large, real-world cohort of hemodialyzed patients, mRNA and viral-carrier COVID-19 vaccines were associated with reduced COVID-19 related mortality. Additionally, we observed a strong reduction of SARS-CoV-2 infection in hemodialysis patients receiving mRNA vaccines.

3 Supplementary Table S1 -Covariates included in the outcome risk score model Table S1.The outcome risk score (ORS) model used to match the vaccinated and unvaccinated patients was assessed with a stepwise logistic regression model (with significance threshold of P-value less than 0.30 for variable entry and 0.15 for variable removal) predicting the SARS-CoV-2 infection in the following 14 days considering the variables listed in the table.

1Figure S2 .
Figure S1.Covariate balance distribution in the sample for mRNA vaccines showing the mean differences (unvaccinated group minus vaccinated group) for the significant covariates of the outcome risk score model.We used Cohen's d for continuous variables and Cramér's V for categorical ones considering acceptable difference of 0.25 or less.

Table S2 .
We explored matching with different calipers of the outcome risk score to balance the tradeoff between patients' similarity within pairs and sample size.The final caliper used was 0.1.
Serum C-Reactive Protein (mg/l) last value within 6 months prior to index date Serum Platelets (no./mm³) last value within 6 months prior to index date Serum Leukocytes (no./mm³) last value within 6 months prior to index date Serum Alanine Aminotransferase (ALT) (IU/l) last value within 6 months prior to index date Serum Potassium (mmol/l) last value within 6 months prior to index date Medications: occurrence of suggestive ATC codes

Table S3 .
We applied data cleansing to 23 continuous variables considering as missing any data that lied outside the listed upper or lower values.The table S3 also shows the amount of missing data after cleansing procedure.We input missing values, resulting from the above-mentioned data cleansing procedure or native in the data, with the national average calculated on the extracted original dataset (i.e.vaccinated and eligible controls).Before matching, eligible control patients are duplicated on each vaccination date in which they were eligible.BMI, body mass index.LTI, lean tissue index.SBP, systolic blood pressure.DBP, diastolic blood pressure.IDWG, interdialytic weight gain.BCM OH, overhydration by the body composition monitor (BCM; Fresenius).BCM relative OH, relative overhydration by the BCM.TSAT, transferrin saturation.

Vaccinated patients by country and vaccine typeTable S4 .
Vaccinated patients in the matched sample, by country and type of vaccine.

Baseline characteristics of the mRNA vaccines cohortTable S5 .
Demographic and clinical characteristics of vaccinated persons and unvaccinated controls at baseline in the sample for mRNA vaccines.Continuous variables are expressed as mean ± standard deviation, categorical variables are expressed as percentage.The mean differences and 95% confidence interval (CI) are related to unvaccinated group minus vaccinated group.For effect size, we used Cohen's d for continuous variables and Cramér's V for categorical ones considering acceptable difference of 0.25 or less.BMI, body mass index.FMC incident, if the patient started the renal replacement therapy not more than 3 months before FMC admission.Online HDF, Online hemodiafiltration.DBP, diastolic blood pressure.IDWG, interdialytic weight gain.BCM OH, overhydration by the body composition monitor (BCM; Fresenius).TSAT, transferrin saturation.ALT, alanine transaminase.6m, 6 months prior to index date.14d, past 14 days prior to index date.30d, past 30 days prior to index date.

Baseline characteristics of the viral-carrier vaccines cohortTable S6 .
Demographic and clinical characteristics of vaccinated persons and unvaccinated controls at baseline in the sample for viral-carrier vaccines.Continuous variables are expressed as mean ± standard deviation, categorical variables are expressed as percentage.The mean differences and 95% confidence interval (CI) are related to unvaccinated group minus vaccinated group.For effect size, we used Cohen's d for continuous variables and Cramér's V for categorical ones considering acceptable difference of 0.25 or less.BMI, body mass index.FMC incident, if the patient started the renal replacement therapy not more than 3 months before FMC admission.Online HDF, Online hemodiafiltration.DBP, diastolic blood pressure.IDWG, interdialytic weight gain.BCM OH, overhydration by the body composition monitor (BCM; Fresenius).TSAT, transferrin saturation.ALT, alanine transaminase.6m, 6 months prior to index date.14d, past 14 days prior to index date.30d, past 30 days prior to index date.

11 Supplementary Table S9 -Cumulative patients with 2 doses of COVID-19 vaccineTable S9 .
Cumulative patients with two doses administered in their follow-up period by vaccine type.The viral-carrier vaccines considered in our study were mostly administered in Eastern Europe countries.In those countries, only Sinovac-CoronaVac and Sputnik V COVID-19 vaccines were available.According to protocols, second doses for both these viral-carrier vaccines should be administered at 2-4 weeks and 3 weeks respectively. *