COVID-19 Vaccine Type and Humoral Immune Response in Patients Receiving Dialysis
Authors: Pablo Garcia, Shuchi Anand, Jialin Han, Maria E. Montez-Rath, Sumi Sun, Tiffany Shang, Julie Parsonnet, Glenn M. Chertow, Brigitte Schiller, Graham Abra
Journal: Journal of the American Society of Nephrology (2021)

Patients receiving dialysis may have a less robust antibody response to coronavirus disease 2019 (COVID-19) vaccination, yet have a 10–15-fold higher risk for COVID-19–associated mortality than the general population.1,2 We previously raised concerns about diminished vaccine responses to the attenuated adenovirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine compared with mRNA vaccines among patients on dialysis, although the number of patients receiving the attenuated adenovirus vaccine was small. In this study, we report qualitative and semiquantitative receptor-binding domain (RBD) antibody responses by vaccine type and dialysis modality in 2367 patients receiving dialysis. Methods In partnership with a nonprofit dialysis provider that serves patients undergoing dialysis in four states (California, Texas, Tennessee, and New Jersey), we evaluated the humoral vaccination response among patients receiving dialysis. From 6020 patients receiving dialysis and undergoing RBD testing, we identified 2367 patients who had results available from a total RBD Ig test before vaccination and a total RBD Ig result available within the 14–60-day period after completing vaccination (Supplemental Figure 1). The dialysis provider made no recommendations regarding type of vaccine, and administration was on the basis of supply availability. More patients residing in the South (Texas and Tennessee) were offered the attenuated adenovirus vaccine due to timing because facilities in the West (California) received vaccines at earlier time points, when attenuated adenovirus vaccines were not yet available. We tested antibody response using the Siemens' total RBD Ig assay, which measures IgG and IgM antibodies.3 Among those with a positive total RBD Ig result, we quantified their antibody response using one of two semiquantitative Siemens RBD IgG assays.4,5 We then defined outcomes as follows: "no seroconversion" indicated lack of change from negative to positive in total RBD Ig antibody, "no RBD IgG response" indicated those with a positive postvaccine total RBD Ig but semiquantitative RBD IgG antibody index value <1, and "diminished RBD IgG response" indicated a positive-vaccine positive RBD total Ig but a semiquantitative RBD IgG index value <10 (Supplemental Methods delineates rationale for index value cut points). Results Of the 2367 patients on dialysis who were fully vaccinated, the proportions receiving the mRNA1273 (Moderna mRNA), BNT162b2 (Pfizer mRNA), and Ad26.COV2.S (Johnson and Johnson, attenuated adenovirus) were 65% (n=1527), 19% (n=440), and 17% (n=400), respectively (Supplemental Table 1). Patients vaccinated with the Ad26.COV2.S vaccine were younger, more likely to be non-Hispanic Black, to have evidence of prior SARS-CoV-2 infection, and reside in the South. Among the 851 participants who were seropositive on the total RBD Ig at a time point before vaccination, testing after vaccination was done at a median of 16 (range 1–60) days after initial assessment of RBD status. Seroconversion to Ad26.COV2.S vaccine occurred later than to the mRNA vaccines (Table 1). However, whether assessed during the 14–28-day window after vaccination or in the 28–60-day window after vaccination, patients receiving the Ad26.COV2.S vaccine had higher likelihood of no seroconversion and no detectable or diminished IgG response compared with those receiving the mRNA vaccines (Table 1). Patients vaccinated with BNT162b2 had higher prevalence of no detectable or diminished IgG response, compared with patients vaccinated with mRNA1273 (Table 1). Table 1. - Prevalence of absent or diminished response among fully vaccinated individuals by vaccine type, RBD status before vaccination, dialysis modality, and overall, between 14 and 28 days and between 29 and 60 days after completion of vaccinea Characteristics Fully Vaccinated Cohort Fully Vaccinated Cohort Days 14 and 28 Days 29 and 60 n=1583b n=1468b Proportion with No Seroconversion on Total RBD Ig (95% Confidence Interval) Proportion with No Detectable or Diminished Response on RBD IgGc (95% Confidence Interval) Proportion with No Seroconversion on Total RBD Ig (95% Confidence Interval) Proportion with No Detectable or Diminished Response on RBD IgGd (95% Confidence Interval) Vaccine type mRNA1273 2.6 (1.7 to 3.7) 5.2 (4.0 to 6.8) 2.0 (1.3 to 3.1) 9.5 (7.7 to 11.7) BNT162b2 4.3 (2.5 to 7.4) 11.4 (8.1 to 15.7) 4.0 (2.1 to 6.2) 22.7 (18.6 to 27.5) Ad26.COV2.S 58.4 (52.6 to 64.0) 16.8 (12.9 to 21.6) 33.3 (27.3 to 40.0) 36.0 (29.2 to 43.5) RBD status before vaccinatione Negative 13.6 (11.6 to 15.8) 10.0 (8.2 to 12.1) 6.8 (5.4 to 8.6) 18.7 (16.3 to 21.4) Positive 12.0 (9.6 to 14.9) 5.9 (4.2 to 8.1) 7.0 (5.0 to 9.7) 11.4 (8.7 to 14.8) Dialysis modality Home 13.7 (9.5 to 19.3) 8.4 (5.2 to 13.3) 9.0 (5.4 to 14.6) 14.7 (10.0 to 21.2) In-center 12.8 (11.1 to 14.7) 8.5 (7.1 to 10.1) 6.6 (5.4 to 8.1) 16.6 (14.6 to 18.8) Vaccine type by RBD status before vaccination mRNA1273 Negative 3.2 (2.1 to 4.9) 6.6 (4.9 to 8.8) 2.1 (1.3 to 3.6) 11.0 (8.7 to 13.8) Positive 1.2 (0.4 to 3.1) 2.5 (1.2 to 4.9) 1.6 (0.6 to 4.2) 5.4 (3.1 to 9.3) BNT162b2 Negative 6.4 (3.6 to 11.2) 13.1 (8.8 to 19.1) 5.1 (2.9 to 8.7) 27.5 (22.1 to 33.7) Positive 1.0 (0.1 to 6.4) 7.8 (3.9 to 14.8) 0.8 (0.1 to 5.8) 13.2 (8.0 to 20.7) Ad26.COV2.S Negative 75.2 (67.1 to 81.8) 22.6 (16.2 to 30.4) 40.8 (31.7 to 50.5) 47.7 (37.4 to 58.1) Positive 43.8 (36.1 to 51.7) 11.8 (7.5 to 17.9) 26.2 (18.7 to 35.3) 24.4 (8.0 to 20.7) Vaccine type by dialysis modality mRNA1273 Home 4.3 (1.8 to 10.0) 1.7 (0.4 to 6.7) 2.0 (0.5 to 7.8) 7.1 (3.4 to 14.2) In-center 2.3 (1.5 to 3.5) 5.7 (4.3 to 7.5) 2.0 (1.2 to 3.2) 9.8 (7.8 to 12.2) BNT162b2 Home 2.6 (0.4 to 16.1) 12.8 (5.4 to 27.3) 5.4 (1.4 to 19.2) 18.9 (9.3 to 34.7) In-center 4.6 (2.6 to 8.1) 11.1 (7.7 to 15.8) 3.5 (1.9 to 6.2) 23.2 (18.8 to 28.3) Ad26.COV2.S Home 55.6 (39.3 to 70.7) 25.0 (13.5 to 41.5) 47.6 (27.8 to 68.2) 42.9 (24.0 to 64.0) In-center 58.8 (52.6 to 64.7) 15.6 (11.6 to 20.6) 31.7 (25.5 to 38.7) 35.1 (27.9 to 43.0) Overall 13.0 (11.4 to 14.7) 8.5 (7.2 to 10.0) 6.9 (5.7 to 8.3) 16.4 (14.5 to 18.5) The overall percentage of patients with mRNA1273, BNT162b2, and Ad26.COV2.S were 65%, 19%, and 17%, respectively; with RBD seropositive before vaccination was 36%, and on in-center hemodialysis before vaccination was 86%. 95% CI, 95% confidence interval.aData are percentage (95% CI) obtained within 14–28 days, or 29–60 days after two doses of either mRNA1273 or BNT162b2 vaccines and a single dose of Ad26.COV2.S vaccine. Diminished classification refers to semiquantitative IgG index value <10.bNumber of patients with an antibody test result within the specified time frame: 889 patients have a test between 18 and 28 days only, 784 patients have a test between 29 and 60 days only, and 684 patients have at least one test in both periods.cTotal n=1532 due to 51 missing semiquantitative IgG result.dTotal n=1326 due to 142 missing semiquantitative IgG result.eRefers to RBD Ig status before vaccination. Across all three vaccine types, patients with a positive RBD total antibody result before vaccination (indicating prior infection) were less likely to have no seroconversion, or absent or diminished RBD IgG response, than patients with a negative RBD total antibody result before vaccination (Table 1). Among persons with an RBD Ig response, median index values were lower for patients receiving the Ad26.COV2.S among patients with a positive RBD total antibody result (Figure 1, A and B). Patients receiving home dialysis with either peritoneal dialysis or home hemodialysis had similar results to patients receiving in-center dialysis (Table 1). There was no difference in response rates by vaccine type among the home versus in-center populations.Figure 1.: RBD IgG responses before and after COVID-19 vaccination by vaccine type among patients receiving dialysis and a detectable total RBD Ig response. (A) The cohort with negative RBD Ig before vaccination, (B) the cohort with positive RBD Ig before vaccination. In these violin plot figures, each marker represents an individual semiquantitative RBD IgG index value by vaccine type in the time period related to vaccination. The index values are plotted on a log-scale, and the violin plot shows a mirrored representation of the distribution of the IgG index values on top of the individual index values. Green circles represent individuals vaccinated with mRNA1273, light blue with BNT162b2, and dark blue with Ad26.COV2.S. The IgG values range from 0.8 to 44, but index values <1 are considered nonreactive, and index values <10 (red dotted line in figures) are considered a "diminished" response. Patients without a detectable RBD IgG are placed in the <1 category (index value is set 0.8). The black boxes represent median values. The data plotted are among the patients with a total RBD Ig (i.e., seroconversion) after vaccination.Discussion In this large cohort of patients receiving dialysis, the prevalence of "no response" or "diminished response" to COVID-19 vaccination varied by vaccine type, with a third of patients receiving the attenuated adenovirus Ad26.COV2.S vaccine failing to seroconvert and an additional third having no detectable or diminished IgG response even 29–60 days after vaccination. Although patients receiving home dialysis represent a cohort with better health and functional status, we observed no difference in response rates by dialysis modality, with similar immunogenicity of the three vaccines in circulation in the United States among patients on in-center versus home dialysis. Limitations of this study include the concentration of patients in four states and nonrandom allocation of vaccine type, although the cohort receiving the attenuated adenovirus vaccine were younger and more likely to have had prior SARS-CoV-2 infection, both factors that likely could have improved response. We only assessed prior SARS-CoV-2 infection by the presence of RBD Ig; we could be thus misclassifying participants as seronegative before vaccination when in fact they had prior SARS-CoV-2 infection. Although a detectable serum antibody response is often equated with immunity, in patients with SARS-CoV-2 infection, data on a correlation between vaccine effectiveness and antibody response are still preliminary.6(preprint),7(preprint) Recent data from participants in the mRNA1273 and ChAdOx1 vaccine trials does suggest that antibody response to RBD or spike protein may be a reasonable proxy for vaccine effectiveness.6(preprint),7(preprint) However, antibody response is one measure of immunity; we were unable to evaluate other aspects of the immune response such as neutralizing antibodies, cellular immunity or the presence of memory B cells. Follow-up of patients with ESKD who were vaccinated for clinical COVID-19 will provide a better estimate of vaccine efficacy by vaccine type. Higher rates of spike protein seroconversion after a third dose of mRNA vaccine were recently reported among solid-transplant organ recipients,8 and in preliminary data among patients on dialysis.9 Although the Biden administration may recommend a booster shot 8 months after completion of the two mRNA vaccines for the general population, no specific recommendation has been put forth for persons who received the Ad26.COV2.S, partly due to lack of population-based data on vaccine effectiveness. Our data—comparing the three vaccines widely circulating in the United States using the same assay—indicate that patients receiving the attenuated adenovirus vaccine had a weaker antibody response in the early period after vaccination, compared with patients receiving the mRNA vaccines. If preliminary data on the correlation between early antibody response and vaccine effectiveness are further confirmed,6,7 our data would support benefit from additional doses among persons receiving dialysis who were given the Ad26.COV2.S. Whether a change in vaccine type is necessary for a subset of patients receiving dialysis who have failed to seroconvert or have demonstrated weak immune response in the early period after vaccination requires further investigation. Disclosures B. Schiller reports having consultancy agreements with Quanta; and reports speakers bureau with AstraZeneca. G. Abra reports receiving honoraria from Akebia; and reports being a scientific advisor or member with Nephrology News and Issues. G. Chertow reports having consultancy agreements with Akebia, Amgen, Ardelyx, AstraZeneca, Baxter, Cricket, DiaMedica, Gilead, Miromatrix, Reata, Sanifit, Unicycive, and Vertex; reports having an ownership interest in Ardelyx, CloudCath, Durect, DxNow, Eliaz Therapeutics, Outset, Physiowave, and PuraCath; reports receiving research funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Data and Safety Monitoring Board service (DSMB); reports being a scientific advisor or member of the Board of Directors of Satellite Healthcare, a not-for-profit dialysis organization, Co-Editor of Brenner & Rector's The Kidney (Elsevier); and Other Interests/Relationships with DSMB service for NIDDK, Angion, Bayer, and ReCor. S. Anand reports serving a Medical Director at a Satellite Healthcare dialysis unit; reports receiving research funding from Applied Pragmatic Research Grant, from Satellite Healthcare; reports receiving honoraria from American Kidney Fund; and reports being a scientific advisor or member of the International Society of Nephrology i3C and Consortium for the Epidemic of Nephropathy in Central America and Mexico. B. Schiller, G. Abra, S. Sun, and T. Shang are employees of Satellite Healthcare. All remaining authors have nothing to disclose. Funding This work was supported by the American Kidney Fund Clinical Scientist in Nephrology Award, the Stanford University School of Medicine Leeds Compassionate Scholar Award (to P. Garcia), and the National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK127138 (to S. Anand) and K24DK085446 (to G. Chertow).