Systematic Review of Safety and Efficacy of COVID-19 Vaccines in Patients With Kidney Disease

Abstract

Chronic kidney disease (CKD) affects 37 million or 15% of the U.S. population and 2 in every 1000 Americans are on dialysis or living with a kidney transplant.1Centers for Disease Control and PreventionChronic Kidney Disease in the United States, 2019. Published online 2019.https://www.cdc.gov/kidneydisease/pdf/2019_National-Chronic-Kidney-Disease-Fact-Sheet.pdfDate accessed: December 1, 2020Google Scholar In 2020, coronavirus disease 2019 (COVID-19) infection became the third leading cause of death for persons 45 through 84 years of age, and individuals with kidney disease are recognized as being at higher risk for severe complications from COVID-19 infection.2Razzaghi H. Estimated County-Level Prevalence of selected underlying medical conditions associated with increased risk for severe COVID-19 illness — United States, 2018.MMWR Morb Mortal Wkly Rep. 2020; : 69Google Scholar,S1 While vaccination is a powerful and cost-effective method to reduce infection-related morbidity and mortality, vaccine efficacy has historically not been rigorously studied in individuals with CKD, and COVID-19 vaccine immunogenicity is largely unknown in this high-risk population. Numerous clinical trials of candidate COVID-19 vaccines have been undertaken; however, it is unknown whether results are generalizable to individuals living with kidney disease, in particular those on dialysis or receiving chronic immunosuppression for treatment of glomerulonephritis or kidney transplantation. We sought to systematically review registered COVID-19 vaccine clinical trials for inclusion of criteria relevant to individuals with kidney disease (Supplementary Methods). As of December 6, 2020, we screened 342 registered COVID-19 vaccine clinical trials (142 from ClinicalTrials.govS2 and 200 from the WHO Clinical Trial databaseS3). Excluded trials included: 118 duplicate trials, 52 trials repurposing non–COVID-19 vaccines (e.g., Bacillus Calmette-Guerin vaccine), and four trials studying vaccination for nonprimary prevention of COVID-19 (Figure 1). Trial characteristics of the resulting 123 unique COVID-19 vaccine trials are displayed in Table 1.Table 1Trial Characteristics of 123 COVID-19 Vaccine Studies Included in the AnalysisAll TrialsPhase 1Phase 2Phase 3N (%)123 (100)aForty-six discrete database enrollments covered more than one phase.78 (63.4)59 (48.0)33 (26.8)Continent of participants Africa2 (1.6)2 (2.6)1 (1.7)0 (0) Asia55 (44.7)37 (47.4)31 (52.5)10 (30.3) Australia6 (4.9)6 (7.7)2 (3.4)0 (0) Europe23 (18.7)13 (16.7)10 (16.9)8 (24.2) North America29 (23.6)20 (25.6)14 (23.7)8 (24.2) South America8 (6.5)0 (0)1 (1.7)7 (21.2)Type of vaccine Live attenuated3 (2.4)1 (1.3)1 (1.7)2 (6.1) Inactivated18 (14.6)8 (10.2)9 (15.3)9 (27.3) mRNA18 (14.6)11 (14.1)10 (16.9)4 (12.1) DNA12 (9.8)10 (12.8)7 (11.9)2 (6.1) Replicating viral vector8 (6.5)7 (9.0)4 (6.8)0 (0) Nonreplicating viral vector34 (27.6)18 (23.1)14 (23.7)12 (36.3) Protein subunit28 (22.8)22 (28.2)13 (22.0)3 (9.1) Virus-like particles2 (1.6)1 (1.3)1 (1.7)1 (3.0)CKD exclusion Patients with GFR <60 ml/min/1.73 m27 (5.7)5 (6.4)3 (5.0)2 (6.1) All patients with CKD17 (13.8)14 (17.9)8 (13.6)1 (3.0) Patients with serious kidney disease41 (33.3)27 (34.6)21 (35.6)11 (33.3) Per investigator discretion based on chronic condition56 (45.5)32 (41.0)27 (45.8)17 (51.5) Patients with CKD not excluded2 (1.6)0 (0)0 (0)2 (6.1)Exclusion from non–live attenuated studiesPatients with immunosuppressive conditions103 (85.8)65 (84.4)48 (82.8)29 (93.5) Patients with immunosuppressive conditions not excluded6 (5.0)3 (3.9)3 (5.2)1 (3.2) Unclear if patients with immunosuppressive conditions are excluded11 (9.2)9 (11.7)7 (12.0)1 (3.2) Patients on any immunosuppressive medications94 (78.3)63 (81.8)49 (84.5)20 (64.5) Patients on immunosuppressive medications other than low-dose steroids21 (17.5)10 (13.0)7 (12.1)10 (32.3) Patients on immunosuppressive medications not excluded3 (2.5)2 (2.6)1 (1.7)1 (3.2) Unclear if patients on immunosuppressive medications are excluded2 (1.7)2 (2.6)1 (1.7)0 (0)Values shown are n (%).a Forty-six discrete database enrollments covered more than one phase. Open table in a new tab Values shown are n (%). Any CKD was explicitly excluded from 16% of trials, “serious renal disease” from 33% of trials, and left to “investigator discretion” in an additional 46% of trials. Few studies used a specific estimated glomerular filtration rate threshold of ≥60 ml/min/1.73 m2 to determine eligibility (6%). In phase 3 trials specifically, 39.4% included patients with any or mild/moderate CKD, with the remaining 60.6% of trials leaving the window open for their exclusion. Individuals receiving immunosuppression for maintenance of a kidney transplant or treatment of an underlying glomerular disease were excluded from 78% of non–live attenuated trials and all live-attenuated trials (n = 3). Exclusion was not explicit in the remaining trials. Similarly, individuals with an immunocompromising disease were excluded from 86% of trials, with the remaining trials having unclear or absent criteria for those with immunocompromising health conditions. In phase 3 trials, 93.5% excluded patients with immunocompromising conditions and 64.5% excluded those on any immunosuppression, and an additional 32.3% excluding any immunosuppression other than low-dose (10 to 20 mg/day) prednisone. Two recently published phase 3 trials of severe acute respiratory syndrome coronavirus 2 vaccines now in clinical use are illustrative of the lack of clarity and inclusion of patients with kidney disease. Pfizer’s trial of BNT162b2 included participants with stable chronic medical conditions; however, only 0.7% of randomized subjects (n = 256) had “renal disease”; a proportion well below the 15% CKD prevalence in the general population.3Polack F.P. Thomas S.J. Kitchin N. et al.Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (6865) Google Scholar Moderna’s trial of the mRNA-1273 vaccine also included participants with stable chronic medical conditions, but has not released data about the prevalence of participants with kidney disease.4Baden L.R. El Sahly H.M. Essink B. et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (4543) Google Scholar Immunocompromised subjects were excluded from both trials. A recently announced phase 3 trial investigating Novavax’s candidate vaccine, NVX-CoV2373, will not exclude prospective participants with stable CKD (NCT04611802), although those receiving chronic immunosuppressants are excluded. Our findings suggest that inclusion of patients with kidney disease in completed and ongoing COVID-19 vaccine studies remains low, with the majority of trials explicitly excluding individuals with “severe” or “chronic” kidney disease and those receiving immunosuppression. Few trials specify an estimated glomerular filtration rate cutoff or CKD stage below which individuals were excluded, leaving room for investigator discretion and lack of clarity for providers to counsel their patients. Our findings have several important implications. First, the low inclusion rates of patients with kidney disease continue to perpetuate the dearth of data on vaccine immunogenicity, efficacy, and safety in the kidney disease population. The Centers for Disease Control and Prevention recommends that individuals with high-risk medical conditions, including those with CKD and those immunocompromised from solid organ transplants, be prioritized for vaccination, without any data on COVID-19 vaccine efficacy in these populations.5Dooling K. Marin M. Wallace M. et al.The Advisory Committee on Immunization Practices’ updated interim recommendation for allocation of COVID-19 vaccine — United States, December 2020.MMWR Morb Mortal Wkly Rep. 2021; 69: 1657-1660Crossref PubMed Google Scholar Currently, trials are underway to study COVID-19 vaccine response in children who were excluded from the original studies and the same should occur for patients with CKD and/or immunosuppressed status. Second, the low rates of CKD inclusion in trials may further exacerbate disparities already pervasive in the pandemic. In the United States, African-Americans and Latinos bear a disproportionate burden of both CKD and of mortality due to COVID-19.6Webb Hooper M. Nápoles A.M. Pérez-Stable E.J. COVID-19 and racial/ethnic disparities.JAMA. 2020; 323: 2466Crossref PubMed Scopus (1198) Google Scholar Without the evidence base to guide vaccination programs in patients with kidney disease, this population could potentially experience lower vaccine effectiveness and hence perpetuate racial and ethnic disparities in COVID-19 disease burden. Existing observational cohorts of patients receiving immunosuppression should strongly consider evaluating vaccine immunogenicity, as large-scale vaccination may make future placebo-controlled studies challenging. Moreover, vaccine immunogenicity and effectiveness at standard vaccine doses and dosing regimens may not yield protective or sustained immune responses in immunosuppressed individuals.7Grzegorzewska A.E. Prophylactic vaccinations in chronic kidney disease: current status.Hum Vaccines Immunother. 2015; 11: 2599-2605Crossref PubMed Scopus (13) Google Scholar,8Krueger K.M. Ison M.G. Ghossein C. Practical guide to vaccination in all stages of CKD, including patients treated by dialysis or kidney transplantation.Am J Kidney Dis. 2020; 75: 417-425Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar,S4 Likewise, test characteristics of assays to evaluate COVID-19 vaccine immunogenicity have been shown to differ between immunosuppressed transplant recipients and the general population, suggesting that neutralizing titers and/or T-cell–based techniques may need to be used to fully understand vaccine immunogenicity in this population.9Prendecki M. Clarke C. Gleeson S. et al.Detection of SARS-CoV-2 antibodies in kidney transplant recipients.J Am Soc Nephrol. 2020; 31: 2753Crossref PubMed Scopus (22) Google Scholar Individuals with glomerular disease represent 7% to 16% of the ∼37 million Americans with CKD.S5 This population has unique risk factors for infection, including prolonged exposure to immunosuppressive medications, systemic inflammation, altered immune cell function, and urinary loss of immunoglobulin and complement factors. As a result, infections requiring health care use occur at a rate approximately 30 times higher among individuals with glomerular diseases compared to the general U.S. population, with lower respiratory infections comprising ∼25% of such infections.S6 Research priorities for COVID-19 vaccination in this patient population should include an investigation of the effect of systemic inflammation, nephrotic-range proteinuria, and immunosuppression exposure, both at the time of vaccination and during disease relapse, on severe acute respiratory syndrome coronavirus 2 immunity. As of 2017, 222,820 people in the United States were living with a kidney transplant.S7 Considerations in immunization programs for solid organ transplant recipients include increased risk of infectious complications of vaccine preventable illnesses, timing of immunization in relation to transplantation, the potential for waning titers of serologic evidence of immunity, and low completion rates of guideline-recommended immunizations both pre- and post-transplantation.S8 Given the higher rates of morbidity and mortality in adult solid organ transplant recipients affected by COVID-19, and the high safety and efficacy of available U.S. Food and Drug Administration–approved COVID-19 vaccines, the benefit of vaccination is widely regarded to outweigh any theoretical risks, despite solid organ transplant recipients being largely excluded from clinical trials. Society guidelines and the Centers for Disease Control and Prevention converge in recommending adult solid organ transplant recipients receive prioritized access to immunization against COVID-19.S9,S10,5Dooling K. Marin M. Wallace M. et al.The Advisory Committee on Immunization Practices’ updated interim recommendation for allocation of COVID-19 vaccine — United States, December 2020.MMWR Morb Mortal Wkly Rep. 2021; 69: 1657-1660Crossref PubMed Google Scholar In the United States, nearly 470,000 individuals receive maintenance dialysis, with the majority choosing in-center treatments rather than home therapies.S7 While there is little doubt that these patients should receive the COVID-19 vaccine, there may be concern about their effectiveness based on data on the durability of the antibody response from influenza vaccines.S11 Dialysis patients should be explicitly included in future clinical trials of COVID-19 vaccines. Furthermore, large dialysis organizations should work with the Centers for Disease Control and Prevention to develop a monitoring plan for markers of immunogenicity (much like for hepatitis B antibody titers) and for COVID-19–related hospitalizations and mortality. Dialysis organizations already have routine laboratory and clinical evaluations in place, and to not make use of this infrastructure would be a lost opportunity. In summary, to ensure maximal trust in and uptake of novel COVID-19 vaccines, clinical trials should be designed to explicitly evaluate the immunogenicity of COVID-19 vaccines in patients with kidney disease. A safety label for patients with kidney disease is insufficient. The nephrology community must take rapid action to implement antibody titer monitoring and vaccine immunogenicity studies in CKD patients, particularly those on dialysis, with autoimmune-mediated kidney disease or receiving immunosuppressive medications. Without a timely and coordinated approach, our patients will be left behind the general population in fighting the COVID-19 pandemic. AM has clinical trial contracts with Boehringer Ingelheim, Calliditas, Duke Clinical Research Institute, and Pfizer, and is a consultant to Bayer. AVK was a consultant for Rockwell Medical in 2020 and received royalties from Up To Date in 2020. RF reports steering committee membership with Vertex Pharmaceuticals. EBW has received funding from Pfizer and Moderna as an investigator for severe acute respiratory syndrome coronavirus 2 vaccine and other vaccine clinical trials. DAG, EK, and AH have nothing to disclose. The authors thank Dr. Samantha Kaplan for her support and assistance with systemic review methodology. Download .pdf (.1 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods and References