Real-World Effectiveness of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA Vaccines in Preventing Confirmed Infection in Patients on Chronic Hemodialysis

Abstract

Background

Persons on chronic hemodialysis have a significantly diminished humoral immune response to SARS-CoV-2 vaccines. Whether this translates to reduced vaccine effectiveness (VE) is unknown.

Methods

We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify all veterans who were tested for SARS-CoV-2 between 26 January and 31 August 2021. Using International Classification of Diseases, 10th edition, codes and attendance at a dialysis clinic/center, we identified those who were on chronic hemodialysis. We used a test-negative, case-control design using a doubly robust logistic regression model to determine the VE of the BNT-162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines in preventing confirmed SARS-CoV-2 infection.

Results

Among 847 199 veterans tested for SARS-CoV-2 between 26 January and 31 August 2021, there were 6076 veterans on chronic hemodialysis. Among those, we identified 1270 cases (580 fully vaccinated) and 2959 controls (2120 fully vaccinated). The overall VE >14 days after the second dose in preventing documented infection was 68.2% (95% CI: 62.6–72.9%). VE was 68.9% (95% CI: 61.9–74.7%) for Pfizer BNT-162b2 and 66.7% (95% CI: 58.9–73.0%) for Moderna mRNA-1273 vaccine. There was no difference in VE by age (<70 vs >70 years), race, or sex. There were no events recorded in persons with a Charlson’s comorbidity index score <2.

Conclusions

VE of 2 doses of current mRNA vaccines in preventing SARS-CoV-2 infection in persons on chronic hemodialysis is lower than historic VE rates in the general population. Effects of additional doses in improving VE in this special population need further study.

In randomized, placebo-controlled clinical trials, mRNA vaccines developed by Pfizer (BNT-162b2) and Moderna (mRNA-1273) demonstrated 94–95% efficacy against symptomatic infection and nearly 100% efficacy against severe disease or death [1, 2]. Subsequent effectiveness studies in real-world settings have reported similarly high rates of effectiveness in preventing confirmed infection and nearly 100% effectiveness in preventing severe disease or death [3, 4]. However, the effectiveness wanes with the passage of time and in patients infected with certain variants of concern [5]. Patients with chronic kidney disease who are on chronic hemodialysis constitute a particularly challenging group due to significant immune suppression. While being at a higher risk of adverse outcomes, including intensive care unit admission and mortality, they have a diminished humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination [6–9]. They also have a higher rate of SARS-CoV-2 breakthrough infections after vaccination [10]. Despite such risk, during the time this study was conducted, persons on chronic hemodialysis were not included in the list of immunocompromised persons recommended for an additional dose of the vaccine [11]. Vaccine effectiveness (VE) of the SARS-CoV-2 vaccines in patients on chronic hemodialysis in the real-world setting is unknown. This information is critical in determining the optimal prevention strategies in this population. To address this gap in knowledge, we determined the effectiveness of the Pfizer BNT-162b2 and Moderna mRNA-1273 vaccines among veterans in care in the US Department of Veterans Affairs healthcare system (VA) who were on chronic hemodialysis.

METHODS

Study Population

In response to the SARS-CoV-2 pandemic, the VA rapidly created a national VA Coronavirus Disease 2019 (COVID-19) Shared Data Resource. Using case definitions and data mapping, which were validated collaboratively across the VA, it contains information on all veterans with a confirmed laboratory diagnosis of SARS-CoV-2 infection within the VA and those who tested outside the VA with a VA clinical note confirming the diagnosis. Updated regularly, the VA COVID-19 Shared Data Resource contains extensive demographic, clinical, pharmacologic, laboratory, vital signs, and clinical outcomes information that is derived from multiple validated sources including the Corporate Data Warehouse and the VA electronic medical records.

For the current study, we identified all Veterans in the VA COVID-19 Shared Data Resource who underwent SARS-CoV-2 testing between 26 January 2021 and 31 August 2021, excluding those with confirmed infections prior to 26 January 2021. Among those tested, we identified persons who were receiving chronic hemodialysis based on presence of 2 or more International Classification of Diseases, 10th edition (ICD-10), codes or at least 2 attendances in a dialysis clinic more than 30 days apart. Cases were defined as patients testing positive (taking the date of first positive test result), whereas controls had only negative tests.

Statistical Analyses

We used a test-negative design to determine the effectiveness of vaccination against confirmed SARS-CoV-2 infection. This design is a widely accepted standard to determine VE in a population after the introduction of a vaccine [12–14]. We have also used this design to report SARS-CoV-2 VE in real-world settings [4, 5, 15–17]. We modeled the effect of vaccines on testing positive using a doubly robust approach, which protects against the misspecification of the propensity score model or the model for the vaccine’s effect, by adjusting for covariates in both models separately [18–20]. The probability of vaccination is modeled using gradient-boosted regression models using age, sex, race, body mass index, testing facility, and Charlson score as input variables [21]. We estimated the adjusted odds ratios (95% confidence intervals [CIs]) from a logistic regression model weighted by inverse probability of vaccination weights, controlling for age, sex, race, body mass index, testing facility, and Charlson score. Vaccine effectiveness was determined using the following formula:

We determined overall VE more than 14 days after the second dose of the vaccine as our primary outcome of interest. We also determined VE separately for patients who were only partially vaccinated by identifying partially vaccinated cases compared with controls who never tested positive. Finally, we determined VE among subgroups by age, sex, race, and Charlson’s comorbidity index score. For all point estimates of VE, we calculated the corresponding 95% CIs [22, 23].

Nearly 97% of the patients in our final study group received the Pfizer BNT-162b2 or the Moderna mRNA-1273. We excluded those who received any other vaccine for our main analyses. As a sensitivity analysis, we performed a 1:1 propensity score–matched analysis followed by conditional logistic regression (accounting for strata of matched pairs) to estimate VE. Details of propensity score modeling and imbalance evaluation are provided in Supplementary Appendices 1 and 2. Propensity score matching was performed using the same propensity scores estimated for the weighted analysis. Nearest-neighbor type matching with caliper 0.25 was performed using the R package matchit (R Foundation for Statistical Computing).

Ethical Considerations

The study was approved by the Institutional Review Board at the VA Pittsburgh Healthcare System. A waiver of informed consent was granted for the study.

RESULTS

We identified 847 199 veterans who were tested for SARS-CoV-2 between 26 January 2021 and 31 August 2021. Among them, there were 6076 veterans who were on chronic hemodialysis, of whom 1843 were excluded from further analyses (1788 tested positive prior to 26 January 2021, 4 due to missing covariate data, 51 because they were vaccinated at sites that were only associated with cases or only controls). The vaccination status of the remaining 4229 cases and controls (prior to the date of first positive test result for cases) is reported in Figure 1, with additional details on propensity score modeling and imbalance evaluation provided in the Supplementary Appendix 3 and Supplementary Figures 1–4. Among the 1270 cases, 580 were fully vaccinated with an mRNA vaccine at least 14 days prior to testing positive, 573 were unvaccinated, and 117 either received the Janssen vaccine, only 1 dose of an mRNA vaccine, or tested positive prior to the 14th day following receipt of their second dose. Among the 2959 controls, 2120 were fully vaccinated with an mRNA vaccine at least 14 days prior to testing positive, 700 were unvaccinated, and 139 either received the Janssen vaccine, only 1 dose of an mRNA vaccine, or tested positive prior to the 14th day following receipt of their second dose. Patients in the latter groups were excluded from the study group for the primary analysis.

The median age was 69 years (interquartile range [IQR]: 62–73 years) for the vaccinated and 67 years (IQR: 60–73 years) for the unvaccinated persons in the primary study group, 97.0% of the vaccinated and 96.0% of the unvaccinated persons were male, and 49.7% of the vaccinated and 46.9% of the unvaccinated persons were Black (Table 1). Common comorbidities included hypertension in 93.0%, cardiovascular disease in 83.7%, and diabetes mellitus in 74.4%. Among the vaccinated group, 56.5% had received the Pfizer BNT-162b2 vaccine and 43.5% had received the Moderna mRNA-1273 vaccine. There was a significant association between testing facility and vaccination status (chi-square, P < .001).

The overall VE more than 14 days after the second dose in preventing documented infection was 68.2% (95% CI: 62.6–72.9%). The effectiveness was 68.9% (95% CI: 61.9–74.7%) for the Pfizer BNT-162b2 and 66.7% (95% CI: 58.9–73.0%) for the Moderna mRNA-1273 vaccine (Table 2). The overall VE was 51.5% (95% CI: 19.6–70.7%) after only 1 dose of the Pfizer BNT-162b2 or Moderna mRNA-1273, and 64.4% any time after the second dose of the mRNA vaccines. There was no difference in VE by age group (<70 vs >70 years), race, or sex (Table 3). There were no events recorded in persons with a Charlson’s comorbidity index score of less than 2.

In sensitivity analyses using a 1:1 propensity score–matched approach, covariate imbalance was higher than for the primary analysis (Supplementary Table 1), and the estimated overall VE was somewhat lower than the primary estimate (Supplementary Table 2). We also estimated the VE over time by calculating the VE for each month after completion of the primary vaccine series (Supplementary Table 3). These results should be interpreted independently of the primary analysis since the controls needed an assigned test-negative date and a look-back at the vaccination status (see footnote in Supplementary Table 3 for details).

DISCUSSION

To our knowledge, this is the first large-scale study of SARS-CoV-2 VE in persons on chronic hemodialysis. We found that the mRNA-based vaccines were effective in preventing documented infection in this group, although their effectiveness was lower than what has been reported for the general population.

Patients on chronic hemodialysis are at a higher risk of SARS-CoV-2 infection, and when infected, are more likely to experience poorer clinical outcomes. This is compounded by the suboptimal humoral response to the currently available SARS-CoV-2 vaccines in these patients. While our results provide reassurance regarding the effectiveness of the mRNA vaccines in preventing documented infection, the observed VE of 68% is lower than the 95% effectiveness in the general VA population [17] and observed in randomized clinical trials [1, 2], although it is sufficiently high to significantly impact the course of disease in this highly vulnerable population. Two factors that significantly reduce VE of the mRNA vaccines against documented infection are passage of time [5] and infection with the Delta variant [24]. The study period for the current study extended through August 2021, when the Delta variant accounted for the overwhelming majority of infections and a substantial proportion of the study population had been vaccinated several months earlier [25].

An overwhelming majority of our study population had comorbidities, the most common being hypertension, diabetes, and cardiovascular disease. The presence of these comorbidities is an independent risk factor for poor clinical outcomes. Vaccine effectiveness among persons with these comorbidities has not been studied. It is unclear whether the lower VE rate in our chronic hemodialysis population was due to these comorbidities, the resultant renal failure, or being on hemodialysis itself. Recently, a third dose of the Pfizer BNT162b2 vaccine has been approved for certain high-risk populations. Early data also demonstrate a significant increase in neutralization of the Beta and the Delta variants after the third dose [26], and recent studies have demonstrated a significant increase in VE in reducing infections and mortality among persons who receive a third dose compared with those who only received 2 doses [27, 28]. Whether a booster will enhance VE in persons on chronic hemodialysis requires further study.

A limitation of our study is the lack of information on SARS-CoV-2 variants of concern. We have previously demonstrated a somewhat lower effectiveness of the Pfizer BNT-162b2 vaccine against the Beta and Delta variants [4, 24]. However, with an overall effectiveness of 68%, the benefit of the vaccine supports its use regardless of the variant type at this time. It is possible that future variants may be less amenable to the current vaccine, which would necessitate altering the vaccines to protect against such potential future variants. We also did not study clinical outcomes such as severe disease or death. Again, a VE of 68% in preventing documented infection necessarily means that a large proportion of complications would be prevented. Varying testing and vaccination practices in different geographic regions can impact the results of such studies. We mitigated this by matching the cases and controls on the geographic location of testing. This matching was done to the level of the center or facility where testing was performed. Since we did not include patients on peritoneal dialysis in our study, our findings cannot be generalized to those patients. Nearly 97% of the study subjects were male; therefore, the results cannot be generalized to females. Our study population was predominantly male and older compared with the general population, and the results should not be generalized to the larger national population.

In conclusion, 2 doses of currently available mRNA vaccines are effective in preventing confirmed SARS-CoV-2 infection in patients on chronic hemodialysis, although the effectiveness is lower than that observed in the general population. Despite the concerns of diminished humoral response, these patients should be prioritized for SARS-CoV-2 vaccination to reduce the risk of infection and its complications.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. Study concept: A. A. B. Study design: A. A. B., V. B. T., F. B. M., and S. B. O. Acquisition and analysis of data: A. A. B., F. B. M., and P. Y. Drafting of the manuscript: A. A. B. Critical revision of the manuscript for important intellectual content: A. A. B., V. B. T., P. Y., O. S. S., S. B. O., and F. B. M. A. A. B. and P. Y. had complete access to data at all times and accept the responsibility of the integrity of this article.

Disclaimer. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the funding agencies.

Financial support. This work was supported by data created by the VA COVID-19 Shared Data Resource and resources and facilities of the Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457. This material is the result of work that is also supported with resources and the use of facilities at the VA Pittsburgh Healthcare System and the central data repositories maintained by the VA Information Resource Center, including the Corporate Data Warehouse.

Potential conflicts of interest. A. A. B. has received grants (to the institution) from Gilead Sciences unrelated to the current work. F. B. M. is supported by K23GM132688 from the National Institutes of Health. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Data availability. Requests for data must be directed to the Veterans Health Administration at the Department of Veterans Affairs. Any request must fulfill all requirements for data sharing according to the existing laws, regulations, and policies of the Department of Veterans Affairs.

Diagnosis codes. International Classification of Diseases 9th and 10th edition codes related to dialysis are provided in Supplementary Appendix 4.

References