key: cord-0298308-cieuiziz
authors: Manley, H. J.; Aweh, G.; Hsu, C. M.; Weiner, D. E.; Miskulin, D.; Harford, A. M.; Johnson, D.; Lacson, E. K.
title: SARS-CoV-2 vaccine effectiveness and breakthrough infections in maintenance dialysis patients
date: 2021-12-21
journal: nan
DOI: 10.1101/2021.12.20.21268124
sha: 2dbb6489cfcae176ef0021db0e9ec87f9c3a6cb1
doc_id: 298308
cord_uid: cieuiziz

nan

Maintenance dialysis patients experience significant COVID-19-associated morbidity and mortality. 1, 2 Vaccines are an effective tool for combatting COVID-19, both in the general population and, likely, among patients dependent on maintenance dialysis, and studies indicate that two doses of a SARS-CoV-2 mRNA vaccine elicit a seroresponse in most (>90%) maintenance dialysis patients, albeit with lower levels than in the general population. [3] [4] [5] Since June 26, 2021, the Delta variant has become the dominant SARS-CoV-2 strain in the United States. 6 In addition to increased virulence, the increased breakthrough rate in fully vaccinated patients during the Delta variant dominant period is also likely due to waning antibody concentrations. In the general population, Tartof et al reported a decrease of protection offered by the BNT162b2/Pfizer vaccine from 93% at baseline to 53% after at least 4 months. 7 We previously reported that 10-15% of dialysis patients did not respond to two doses of an mRNA vaccine; additionally, among initial responders to vaccine, more than half experience waning immunity by 4-6 months, particularly those whose initial response was lesser. 5, 8 The impact of lesser initial vaccine response and subsequent waning antibody levels on clinical outcomes among maintenance dialysis patients is not known. Additionally, the impact of the Delta variant on vaccine effectiveness in this population is unknown. Accordingly, we describe the incidence of COVID-19 diagnoses and COVID-19 related hospitalization or death among unvaccinated, partially vaccinated and fully vaccinated adult dialysis patients treated by a national dialysis provider within the US between February 1 and October 2, 2021, evaluating both the pre-Delta and Delta dominant periods. Additionally, among the subset of vaccinated patients with available SARS-CoV-2 vaccine immunoglobulin G spike antibody (anti-spike IgG) titers who were diagnosed with 'breakthrough' COVID-19, we explore the association between antibody levels and clinical outcomes.

Dialysis Clinic, Incorporated (DCI) is the largest non-profit provider of kidney care and dialysis care in the United States, operating 260 outpatient dialysis clinics in 29 states, 20 chronic kidney disease clinics in 5 states, and 3 organ procurement organizations in 3 states. All adult (age ≥18 years) maintenance dialysis patients treated between February 1 and October 02, 2021 in DCI clinics contributed time-at-risk, excluding patients with known COVID-19 diagnosis prior to February 1, 2021, transient patients (e.g. visiting from a non-DCI clinic) and/or patients treated for acute kidney injury who were not certified as end-stage renal disease (ESRD).

All maintenance dialysis patients treated at DCI outpatient facilities, including home dialysis and in-center dialysis patients, are screened at each clinic encounter for COVID-19 symptoms and any known exposure to infected person(s). These symptoms include fever (≥100 degrees), sore throat, new or worsening cough or shortness of breath, and loss of taste or smell. The vast majority of maintenance dialysis patients (>85%) are treated by in-center dialysis and are screened before each treatment, most often thrice weekly, while home dialysis patients typically are screened once or twice each month during visits to the dialysis facility. Any patient who screens positive is classified as a "Patient Under Investigation" and is tested for SARS-CoV-2 either locally or through the DCI laboratory. Most dialysis patients have multiple comorbid illnesses and have frequent contact with the healthcare system where they are tested even when asymptomatic.

Similarly, many patients who are residents of congregate home settings, such as nursing homes, are frequently screened and tested as well. The diagnosis of COVID-19 is entered into DCI's electronic health record (EHR), often based on a report of a positive SARS-CoV-2 test result, which if performed via the DCI laboratory, utilizes a reverse transcriptase-polymerase chain reaction (RT-PCR) Cobas SARS-CoV-2 Assay [Roche Diagnostics].

The DCI central laboratory assesses serum anti-spike IgG antibody against the receptor binding domain of the S1 subunit of SARS-CoV-2 spike antigen using a US-FDA-EUA-approved chemiluminescent assay (ADVIA Centaur® XP/XPT COV2G). This semi-quantitative assay has a range between 0 and ≥20. The manufacturer defined threshold for a minimum antibody detection level is ≥1. 9 This test is available for physicians to order either one time or as part of a clinical testing protocol, but is not measured in all maintenance dialysis patients routinely, per present CDC guidelines. 10 The clinical testing protocol follows monthly anti-spike IgG titers using residual blood from routine monthly lab draws until the level is <1 for two consecutive months or for up to 12 consecutive months.

New COVID-19 diagnoses were documented based on screening as described above, or from contacts with other healthcare settings, such as hospitals and emergency department visits or clinic visits. All new COVID-19 diagnoses that occurred during the study period were each assigned to the appropriate vaccination status. For all breakthrough cases, defined as a COVID-19 diagnosis in a patient deemed fully vaccinated, the clinic was contacted to verify the reason why the patient was tested for SARS-CoV-2: for exposure to a known COVID-19 infected person or for symptoms/signs consistent with COVID-19 or as required by a non-dialysis clinic/hospital protocol prior to providing a COVID-unrelated service/procedure (e.g. vascular access surgery) or as part of protocolized screening (e.g. nursing home). COVID-19 related hospitalizations or deaths were defined by documented primary diagnosis for the episode of care as COVID-19

(ICD-10 code U01.7). 

Each eligible patient who received treatment for at least one day during the study period contributed days-at-risk. Patients could move from being unvaccinated (defined by the CDC to include the period extending up to 13 days after the first vaccine dose) 3 to partially vaccinated (for mRNA vaccines only; defined by the CDC as the period starting 14 days after the first mRNA vaccine dose up to 13 days after the 2 nd mRNA vaccine dose) to fully vaccinated (≥14 days after completing the manufacturer recommended final dose). Patients could contribute days-at-risk for each applicable category as long as they remained SARS-CoV-2 uninfected. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Case rates per 10,000 days at-risk and the composite outcome of COVID-related hospitalization or death for each vaccine status, and, in additional analyses among those fully vaccinated, for each vaccine type, were compared using a time dependent Cox proportional hazard models with unvaccinated patients as the reference group. The statistical model was subsequently adjusted for all baseline patient characteristics that differed at baseline among vaccination status within each time period ( Table 1) . Each patient's state and county of residence was also used to adjust for geotemporal variability in the intensity of the epidemic and likelihood to follow mask wearing, social distancing and vaccine recommendations by incorporating daily county-level COVID-19 case rates and the percentage of Biden voters during 2020 US Presidential election, respectively. 11-13 Vaccine effectiveness and 95% CIs were calculated using the following: (1 -HR) x 100. 14 We also determined case rates and vaccine effectiveness in a subset of patients vaccinated during the Delta variant dominant period.

Among patients with breakthrough COVID-19 diagnoses, we evaluated the subset with available anti-spike IgG titer results prior to the COVID-19 diagnosis. Results subsequently were deidentified and aggregated, and the association between the most proximate anti-spike IgG titer result and clinical outcomes was evaluated descriptively. Case rates per 10,000 days and adjusted hazard ratios for COVID-19 infection and composite for COVID-related hospitalization or death were calculated for anti-spike IgG values <1 (versus ≥1), < 2 (versus ≥2), <7 (versus ≥7) and <10 (versus ≥10). We selected the various cut-points to compare outcomes in those with undetectable levels of < 1 (reported by assay manufacturer) or < 2 (internal DCI laboratory validation) , at assay threshold one index value above where COVID-related hospitalization or death not reported (anti-All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.20.21268124 doi: medRxiv preprint spike IgG value ≥7) and assay level recently reported as having higher odds for breakthrough infection (anti-spike IgG < 10). 15 This study was reviewed and approved by the WCG IRB Work Order 1-1456342-1. Statistical analyses were performed using SAS v9.4. with BNT162b2/Pfizer, while 3,794 (24%) were unvaccinated. Patients mean age (years) and vintage (months) were 63±15 years old and 45 ± 56 months, respectively. Majority (87%) patients were receiving in-center hemodialysis, 59% had diabetes and 20% were considered immunocompromised ( Table 1) .

There were 967 documented COVID-19 cases, with 511 (53%) occurring in unvaccinated patients and 579 (60%) occurring during the Delta dominant period. COVID-19 rates per 10,000 patient days and vaccine effectiveness for each time period between February 1 and October 2, 2021 are shown in Table 2 . There were 362 (37%) cases that occurred among those considered fully vaccinated, with most of these breakthrough cases (n=335; 93%) occurring during the Delta dominant period; 92 (25%) of patients with breakthrough cases met CDC criteria for All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Figure S1 Panel B) .

Over the entire study period and compared to unvaccinated patients, the COVID-19 case rate was ( Table S1) Vaccination status and Vaccine Effectiveness against COVID-19 related hospitalization or death All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Anti-spike IgG levels were available in 2,451 (22%) fully vaccinated patients over the study period. At each anti-spike IgG threshold evaluated, the lower anti-spike IgG level was associated with higher case rates per 10,000 days and adjusted hazard ratios for both infection ( Table 4 ) and COVID-related hospitalization or death ( Table 5) .

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. There were 80 breakthrough infections (BNT162b2/Pfizer N=32, mRNA-1273/Moderna N=28, and Ad26.COV2.S/Janssen N=20) with the level most proximate to diagnosis measured a median (IQR) of 16 (8, 27 ) days prior to COVID-19 diagnosis. The frequency of COVID-19 cases requiring hospitalization across anti-spike IgG levels is shown in Figure 1 . Half of breakthrough cases and the majority of COVID-related hospitalizations (20 of 29) occurred when the anti-spike IgG level was undetectable while an additional 4 hospitalizations and 12 total cases occurred at a level < 2, with the remaining hospitalizations occurring at antibody levels between 1 and 6. There were 8 patients with undetectable anti-spike IgG levels that experienced a COVID-19 related death following a hospitalization event (Figure 1 ). infection. For COVID-related hospitalization, vaccine effectiveness during presumed Delta variant cases remained high when compared to unvaccinated patients. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.20.21268124 doi: medRxiv preprint Among vaccine types there were marked differences. Overall and during each time period evaluated, vaccine effectiveness for COVID-related hospitalization or death was highest with mRNA-1273/Moderna, then BNT162b2/Pfizer and finally Ad26.COV2.S/Janssen when compared to those unvaccinated. In our study population Ad26.COV2.S/Janssen vaccine was not only associated with lower antibody response, 5, 8 but likely was associated with higher breakthrough and COVID-19 related hospitalization rates than the mRNA vaccines, particularly when compared to the mRNA-1273/Moderna vaccine.

While the CDC did not specifically designate dialysis patients as immunocompromised persons who should receive routine administration of a third COVID-19 mRNA vaccine dose, they cited dialysis patients as a possible immunocompromised group where clinical opinion is important. 16 Similar to the general population, the CDC recommends that maintenance dialysis patients receive a booster dose six months or later after full vaccination with mRNA vaccine or a booster of the Ad26.COV2.S/Janssen vaccine two months after initial vaccination. In our results, 50% of breakthrough cases occurred within 4.5 months of full vaccination and 90% of cases occurred within six months post full vaccination status, consistent with a marked increase between 4.5 and 6 months. Consistent with this, increasing time (days) since full vaccination status was associated with increased risk for COVID-19 related hospitalization or death, especially during the Delta period where most patients were several months beyond attaining full vaccination status.

Recognizing that not all maintenance dialysis patients produce anti-spike IgG antibodies to the same degree and that antibodies decline over time, the timing of third dose or a booster should be not arbitrarily be based on time. Since anti-spike IgG antibody titers correlate with COVID All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 19 However, adopting a test and treat approach with routine measurement of anti-spike IgG levels followed by additional doses of vaccine as needed to maintain adequate antibody levels is warranted. Relevantly, we observed high frequency of COVID-19 breakthrough cases and more frequent hospitalization among those with low antibody levels (<7). Recently Anand et al. reported that anti-spike IgG value < 10 were associated with higher odds for breakthrough infection. 15 In our results (Tables 3 and 4) , 79% breakthrough infections occurred in patients having anti-spike IgG value < 10. Additionally, all COVID-related hospitalizations occurred at anti-spike IgG < 6 and COVID-related deaths when antibody levels were undetectable (Figure 1 ). This approach, where vaccine administration is predicated on antibody levels, has been well-demonstrated with hepatitis B vaccination among dialysis patients. 20 Study strengths include the national population of a mid-size dialysis provider in the US with real world clinical outcomes. However, there are limitations associated with this study. Due to the observational design, residual biases (e.g., misclassification of vaccine exposure in patients vaccinated outside the clinic, inability to identify all asymptomatic infections) and confounding may exist. Randomized clinical trials comparing individual COVID-19 vaccines head-to-head are not likely to be performed in this population. The electronic health records do not contain standardized documentation of COVID-19 symptoms and therefore we could not estimate vaccine effectiveness with regard to mitigating or tempering severity of symptoms. Although the model adjusted for likelihood to follow mask, social distancing and vaccine recommendations All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 21, 2021. ; throughout the US by adjusting for state and county level presidential election voting records, individual patient actual adherence to those recommendations is not known. Finally, we did not know the specific SARS-CoV-2 variant for each infection and attributed all infections to the Delta variant after June 26, 2021.

In conclusion, SARS-CoV-2 vaccines are effective in maintenance dialysis patients, reducing the risk of both COVID-19 cases and COVID-related hospitalization or death. COVID-19 cases increased during the Delta variant dominant period and current immunosuppression criteria are limited in identifying dialysis patients at highest breakthrough risk. Further research is needed to evaluate the potential utility of antibody titer monitoring to determine patients at highest risk for COVID-19 and to dictate the timing of additional vaccine administration.

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.20.21268124 doi: medRxiv preprint preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.20.21268124 doi: medRxiv preprint preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.20.21268124 doi: medRxiv preprint

COVID-19 Among US Dialysis Patients: Risk Factors and Outcomes From a National Dialysis Provider

Epidemiology and Outcomes of COVID-19 in Home Dialysis Patients Compared with In-Center Dialysis Patients

Control and Prevention: Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States

Humoral Response to the Pfizer BNT162b2 Vaccine in Patients Undergoing Maintenance Hemodialysis

Immunogenicity of SARS-CoV-2 Vaccine in Dialysis. medRxiv

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system

Vaccine Antibody Response and Breakthrough Infection in Patients Receiving Dialysis

Prevention: COVID-19 Vaccines for Moderately to Severely Immunocompromised People

Evidence for antibody as a protective correlate for COVID-19 vaccines

Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

Control and Prevention: Summary Document for Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States

Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older -United States

All rights reserved. No reuse allowed without permission

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity