key: cord-0936572-lpeab2hh
authors: Yau, K.; Abe, K. T.; Naimark, D. M.; Oliver, M. J.; Perl, J.; Leis, J. A.; Bolotin, S.; Tran, V.; Mullin, S.; Shadowitz, E.; Garnham-Takaoka, J.; Quinn De Launay, K.; Takaoka, A. T.; Straus, S. E.; McGeer, A. J.; Chan, C. T.; Colwill, K.; Gingras, A.-C.; Hladunewich, M. A.
title: The Humoral Response to the BNT162b2 Vaccine in Hemodialysis Patients
date: 2021-05-27
journal: nan
DOI: 10.1101/2021.05.24.21257425
sha: eb32eed515f704231ccace180aa3d94507302dfe
doc_id: 936572
cord_uid: lpeab2hh

Importance: Hemodialysis patients have an exceptionally high mortality from COVID-19 and this patient population often has a poor response to vaccinations. Randomized controlled trials for COVID-19 vaccines included few patients with kidney disease, therefore vaccine immunogenicity is uncertain in this population. Objective: Evaluate the SARS-CoV-2 antibody response in chronic hemodialysis patients following one versus two doses of BNT162b2 COVID-19 vaccination compared to health care worker controls and convalescent serum. Design: Prospective observational cohort study. Setting: Single centre study in Toronto, Ontario, Canada. Participants: 142 in-centre hemodialysis patients and 35 health care worker controls. Exposure: BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. Main Outcomes and Measures: SARS-CoV-2 IgG antibodies to the spike protein (anti-spike), receptor binding domain (anti-RBD), and nucleocapsid protein (anti-NP) were measured in 66 hemodialysis patients receiving one vaccine dose following a public health policy change, 76 patients receiving two vaccine doses, and 35 health care workers receiving two vaccine doses. Results: Detectable anti-NP suggestive of natural SARS-CoV-2 infection was detected in 15/142 (11%) of patients at baseline while only three patients had prior RT-PCR confirmed COVID-19. Two additional patients contracted COVID-19 after receiving two doses of vaccine. In patients receiving a single BNT162b2 dose, seroconversion occurred in 53/66 (80%) for anti-spike and 35/66 (55%) for anti-RBD by 28 days post dose, but only 15/66 (23%) and 4/66 (6%), respectively attained a robust response as defined by reaching the median level of anti-spike and anti-RBD in convalescent serum from COVID-19 survivors. In patients receiving two doses of BNT162b2 vaccine, seroconversion occurred in 69/72 (96%) for anti-spike and 63/72 (88%) for anti-RBD by 2 weeks following the second dose while 52/72 (72%) and 43/76 (41%) reached the median convalescent serum level of anti-spike and anti-RBD, respectively. In contrast, 35/35 (100%) of health care workers exceeded the median level of anti-spike and anti-RBD found in convalescent serum 2-4 weeks after the second dose. Conclusions and Relevance: This study confirms poor immunogenicity 28 days following a single dose of BNT162b2 vaccine in the hemodialysis population, supporting adherence to recommended vaccination schedules, and avoiding delay of the second dose in these at-risk individuals.

Importance: Hemodialysis patients have an exceptionally high mortality from COVID-19 and this patient population often has a poor response to vaccinations. Randomized controlled trials for COVID-19 vaccines included few patients with kidney disease, therefore vaccine immunogenicity is uncertain in this population.

Objective: Evaluate the SARS-CoV-2 antibody response in chronic hemodialysis patients following one versus two doses of BNT162b2 COVID-19 vaccination compared to health care worker controls and convalescent serum.

Design: Prospective observational cohort study.

Setting: Single centre study in Toronto, Ontario, Canada. Two additional patients contracted COVID-19 after receiving two doses of vaccine. In patients receiving a single BNT162b2 dose, seroconversion occurred in 53/66 (80%) for anti-spike and 35/66 (55%) for anti-RBD by 28 days post dose, but only 15/66 (23%) and 4/66 (6%), respectively attained a robust response as defined by reaching the median level of anti-spike and anti-RBD in convalescent serum from COVID-19 survivors. In patients receiving two doses of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint BNT162b2 vaccine, seroconversion occurred in 69/72 (96%) for anti-spike and 63/72 (88%) for anti-RBD by 2 weeks following the second dose while 52/72 (72%) and 43/76 (41%) reached the median convalescent serum level of anti-spike and anti-RBD, respectively. In contrast, 35/35 (100%) of health care workers exceeded the median level of anti-spike and anti-RBD found in convalescent serum 2-4 weeks after the second dose.

This study confirms poor immunogenicity 28 days following a single dose of BNT162b2 vaccine in the hemodialysis population, supporting adherence to recommended vaccination schedules, and avoiding delay of the second dose in these at-risk individuals.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 27, 2021.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has resulted in a devastating global pandemic. Among those most severely affected are patients on maintenance hemodialysis who must visit facilities at least thrice weekly for life sustaining treatment resulting in a five times greater risk for infection than the general population. 1 Despite adherence to public health guidance, outbreaks have occurred in dialysis units. 2 Further, patients on dialysis are at greater risk for severe COVID-19, with 63% of chronic dialysis patients with COVID-19 requiring hospitalization and a case fatality rate of 29% in Ontario, Canada. 1 Confirmatory data from the US Renal Data System found mortality among hemodialysis patients in early 2020 was 16-37% higher than in 2017-2019. 3 Dialysis patients frequently have diminished immune response to vaccination compared with the general population, as observed during hepatitis B vaccination. 4 Studies of natural COVID-19 infection in dialysis patients found waning antibody concentrations by three months, raising the possibility that dialysis patients may not develop an adequate vaccination response. 5 Finally, randomized controlled trials for the BNT162b2 vaccine included few patients with kidney disease. 6 Therefore data on vaccine immunogenicity are lacking in this high-risk population.

Two doses of BNT162b2 vaccine were administered 21 days apart in randomized controlled trials. However, due to vaccine shortages, countries including the United Kingdom and Canada have prioritized first dose vaccination of the general population, 7 while delaying the second dose for up to 3-4 months, offering a natural experiment for comparison of one versus two doses. To investigate the humoral response conferred by COVID-19 vaccination in the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint hemodialysis population, we conducted a prospective observational study measuring SARS-CoV-2 IgG antibody levels following one versus two doses of vaccine.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint

In-centre hemodialysis patients age ≥18 years, including those with prior COVID-19, were eligible for this single centre prospective observational study to evaluate SARS-CoV the sensitivity and specificity of each assay was determined by precision-recall analysis from pre-COVID negative and convalescent controls. 8, 9 Antibody levels were reported as relative ratios to a synthetic standard included as a calibration curve on each assay plate. Thresholds for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint positivity (seroconversion) were determined by aggregating data from negative controls and calculating the mean + 3 standard deviations. Relative antibody levels were also compared to the median levels of convalescent serum taken 21-115 days post symptom onset in patients with COVID 19; expression of vaccination-induced antibody levels to convalescent individuals helps to define correlates of protection. 10 The association between reactogenicity following second vaccine dose and the proportion of patients with anti-spike or anti-RBD seroconversion two weeks following second dose was assessed by a Chi-Squared test.

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The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint

Among 142/157 (90%) consenting in-centre hemodialysis patients, the median age was 72 years and 48/142 (34%) were female (Table 1) The presence of reactogenicity was associated with anti-RBD seroconversion (p<0.001) but not anti-spike seroconversion. Two patients contracted COVID-19 following two doses of vaccine despite both having an anti-RBD antibody response above convalescent serum levels prior to anti-NP seroconversion. Both patients were hospitalized, but did not experience severe disease.

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The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint

This prospective serology study found that while high rates of seroconversion were observed, consistent with other studies in hemodialysis patients, 12 a robust anti-RBD response defined as reaching convalescent serum levels was seen in less than 10% of patients 28 days after a single dose. In contrast, two weeks after the second dose, 60% of hemodialysis patients had anti-RBD antibodies levels comparable to those achieved by infected patients. Anti-RBD response was lower than anti-spike response, which is of importance as anti-RBD may better correlate with viral neutralization. 9 While our study did not evaluate cell-mediated immunity, a good anti-RBD response is required for adequate cell-mediated response. 13 Interestingly, we found that symptoms following the second vaccine dose were associated with anti-RBD seroconversion and may help identify patients who develop some protection.

The response to the second dose, however, was notably weaker than in the HCW controls wherein 100% generated robust anti-RBD antibodies. This finding is similar to other compromised populations. In Canada, patients with malignancy and solid organ transplant receive two doses per manufacturer guidelines as studies demonstrating poor humoral response to one dose vaccination led to policy changes. 14, 15 With widespread global vaccine shortages, it is critical that we identify vulnerable populations. This study confirms a poor humoral response following a single dose of BNT162b2 COVID-19 vaccination in hemodialysis patients, and demonstrates the critical importance of the second dose, which should not be delayed in this vulnerable population.

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We would like to thank Anny Gonzalez and Tatjana Sukovic for coordinating this study and the Sunnybrook Hemodialysis Staff for assisting with sample collection. We would also like to thank . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The median level of antigen in convalescent serum taken 21-115 days post-symptom onset is considered a robust antibody response and are 1.38,1.25, and 1.13 for anti-spike, anti-RBD, and anti-NP antibodies respectively. c Second dose was administered 21 days following first dose.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint Antibody levels are reported as relative ratios to synthetic standards. The samples are grouped into two cohorts who received one (n=66) or two doses (n=76) of vaccine. Dots represent individual serum samples collected at the indicated times, and the samples from the same patients are connected by lines. Green dots indicate individuals with prior RT-PCR confirmed SARS-CoV-2 infection. Seroconversion threshold represents a positive test and are 0.19, 0.186, and 0.396 for anti-spike, anti-RDB, anti-NP antibodies, respectively. The median level of antigen in convalescent serum taken 21-115 days post-symptom onset is considered a robust antibody response and is 1.38, 1.25, and 1.13 for anti-spike, anti-RBD, and anti-NP antibodies, respectively. Healthy control workers (n=35) received two doses of vaccines with serologic measurement 2-4 weeks following dose 2. Abbreviations: HCW, health care worker; NP, nucleocapsid protein; RBD, receptor binding domain.

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The copyright holder for this preprint this version posted May 27, 2021. ; https://doi.org/10.1101/2021.05.24.21257425 doi: medRxiv preprint

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