key: cord-0273760-pjhpvpht
authors: Rosa-Diez, G.; Papaginovic-Leiva, M. M.; Lombi, F.; Crucelegui, M. S.; Martinez, R. D.; Trimarchi, H.; Schiavelli, R.; Grizzo, M.; Rano, M.; . Heguilen, R. M.; Jones, R. A.; Gonzalez-Paganti, L.; Ferrari, M.; Zingoni, P.; Kjohede, V.; Geffner, J. R.; Ferrante, D.; Gonzalez Bernaldo de Quiros, F.; Pagotto, V.
title: Safety and Effectiveness of COVID-19 SPUTNIK V Vaccine in Dialysis Patients
date: 2021-10-25
journal: nan
DOI: 10.1101/2021.10.21.21265349
sha: dfb35a114cf58e70e8f7f7970d502701890ded93
doc_id: 273760
cord_uid: pjhpvpht

Given the vulnerability of people with chronic kidney disease to COVID-19, nephrology societies have issued statements calling for prioritization of these patients for vaccination. It is not yet known whether COVID-19 vaccines confer the same high level of protection in patients with kidney disease. The aims of this study were to evaluate the safety measured by the events supposedly attributed to vaccines and the effectiveness evaluated by the presence of antibodies in dialysis patients immunized with the COVID-19 Sputnik V vaccine. Methods: multicenter, observational, and analytical study of a prospective cohort of hemodialysis patients in the Autonomous City of Buenos Aires with a vaccination plan. Patients older than 18 years on dialysis who received both components of the COVID-19 vaccine were included. Results: 491 patients included in the safety analysis. ESAVI with either the first or second component was detected in 186 (37.9% 95% CI 33.6%-42.34%). The effectiveness analysis measures of antibodies against SARS-Cov-2 were performed in 102 patients, 98% had positive IgG against SARS-Cov-2 antibodies 21 days after the second component. In patients with COVID-19 prior to vaccination, antibodies at day 21 after the first component reached almost the highest levels compared to those patients who did not have COVID-19, and the rise between the last measures was lower than patients without COVID-19. Conclusion: Dialysis patients constitute a vulnerable population for SARS-Cov-2 infection, beyond the recommendations that were implemented by dialysis units, full vaccination is a priority and necessary. The Sputnik V vaccine has been shown to be safe and effective in this patient population.

The World Health Organization (WHO) (1) recommends vaccination against coronavirus disease 19 (COVID-19) as a fundamental primary prevention tool to limit the health and economic effects of the pandemic. As a consequence, having effective and safe vaccines in the short term, which can be used in a national strategy, will help to reduce the incidence of illness, hospitalizations and deaths related to and help to gradually reestablish a new normality in the functioning of our country.

On December 23, the National Administration of Medicines, Food and Medical Technology (ANMAT) submitted the report on the Sputnik V vaccine to the Ministry of Health of the Nation to advance in the Emergency Authorization of a batch series of Sputnik V vaccine, which according to preliminary phase 1/2 and 3 studies confer immunogenicity (2, 3) .

After the emergency authorization of the Sputnik V vaccine, other vaccines were approved for use, including the recombinant ChAdOx1-S vaccine from AstraZeneca. (4, 5) and Sinopharm vaccine (4) . Whilst all vaccines demonstrated efficacy in their publications (2) (3) (4) 6) , they come from phase 3 studies, which evaluate the efficacy of the vaccine. Effectiveness refers to the protection provided by the vaccine as measured in observational studies that include people with underlying medical conditions who have been receiving vaccines from different healthcare providers under real-world conditions. So far there are no observational epidemiological studies that reveal the behavior of those vaccinated for COVID-19 in Argentina and therefore evaluating their effectiveness and reactogenicity. The safety profile of vaccines and reactogenicity are fundamental elements for the acceptance of vaccines in the population. If a vaccine is perceived as too reactogenic, the subject may refuse additional doses or the healthcare professional may choose not to recommend it, which can lead to incomplete protection of the individual and low coverage of the vaccine in the population (7, 8) .

Maintaining high vaccine coverage is critical to the success of vaccination programs.

A few years ago, he was able to consider the concept "no pain, no gain", assuming that, if a vaccine does not produce inflammation as a "proxy" for pain, the immune response achieved was poor, leaving a common belief that a reaction in place of injection to a vaccine is a predictive sign of a desirable vaccine response (9) .

The Ministry of Health of the Nation (10), has designed the Strategic Plan for vaccination against COVID-19 in Argentina (11) , being one of its specific objectives being establish essential priority axes to evaluate vaccination goals: coverage rates, continuous monitoring of safety and effectiveness of vaccines, in correlation with the epidemiological impact that vaccination produces on COVID-19 (11) .

Kidney disease substantially increases the risk of severe COVID-19. Considering the relative efficacy of the current therapeutic arsenal available to reduce hospitalizations and mortality from COVID-19, and effective and safe vaccination are currently the only realistic options to curb the ongoing pandemic and reduce SARS CoV-2 infections.

Throughout 2020, several vaccines were licensed for emergency use, and many more are in development (12) .

Dialysis patients constitute a population at risk, not only because of their vulnerability to COVID-19, but because they cannot comply with social isolation since they must go to dialysis every three weeks. The COVID Registry of the Argentine Dialysis Registry showed that COVID infection affected 12% of the population on dialysis to date, and that mortality was 11 times higher compared to the general population (13) .

Given the vulnerability of people with chronic kidney disease (CKD) to COVID-19, leading nephrology societies such as the UK Kidney Association and the US National Kidney Foundation have issued statements calling for prioritization of these patients for vaccination. The Argentine Society of Nephrology presented it in a timely manner All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 25, 2021. ;  to the Ministry of Health of the Nation, which has considered the priority of this patient population. However, it is not yet known whether COVID-19 vaccines confer the same high level of protection in patients with kidney disease as reported for participants in recent trials, who were generally healthy (14) .

Patient characteristics such as age, sex, type of kidney disease, and treatment regimen can also influence the inmunological response to vaccines. In patients with weak or no induction of T-cell seroconversion and / or immunity after vaccination, theoretical options include an additional booster dose, administration of a different vaccine platform (15) Seroconversion after confirmed infection would approach 100% in the dialysis population, but the durability of this immune response and the degree to which it translates into protective immunity remain unclear. Some studies indicate that SARS-CoV-2 IgG titers decrease substantially 3 months after diagnosis (16) . Ongoing research should elucidate whether certain vaccines offer specific benefits for people on chronic dialysis. The aims of this study were to evaluate the safety measured by the events supposedly attributed to vaccines and the effectiveness evaluated by the presence of antibodies in dialysis patients immunized with the COVID-19 Sputnik V vaccine.

Ethics statement: The study was approved by the Ethics Committee of the Alberto C Taquini Institute for Translational Medicine Research of the Faculty of Medicine of the University of Buenos Aires. For the effectiveness study, based on the measurement of antibodies, informed consent was requested. The study protocol was registered in ClinicalTrials.gov Identifier: NCT04944433

A multicenter, observational and analytical study was carried out on a prospective cohort of hemodialysis patients in the Autonomous City of Buenos Aires with a vaccination plan. The date of inclusion in the cohort was the start date of vaccination.

Patients older than 18 years on dialysis who received both components of the COVID-19 vaccine were included. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

Data related to safety were collected, events allegedly attributed to vaccines and immunizations (ESAVI) after receiving the Sputnik V vaccine, the history of COVID-19 prior to vaccination and the presence of symptomatic COVID-19 after it. Demographic and kidney disease-related (type of dialysis: hemodialysis or peritoneal; kidney transplant; time in dialysis) data were obtained This information was collected by the health professionals of each center who are in charge of the dialysis sessions of the patients using an epidemiological file designed for the study was used.

Data referring to the effectiveness was the measurement of antibodies type immunoglobulin G (IgG) against SARS-Cov-2. The "COVIDAR IgG" test, which is registered in ANMAT, was used for the determination of antibodies. The test detects in blood and serum antibodies that the immune system produces for the new coronavirus, specifically against two viral antigens: the spike protein (S) and the receptor-binding domain (RBD). It is performed on plates that allow testing 96 sera at the same time using the technique known as ELISA, the same one used, for example, for the detection of HIV infection and hepatitis B. The COVIDAR IgG test detects the presence of IgG qualitatively and semi-quantitatively. In the semi-quantitative determination, the values are measured in absorbance levels (DO) with a maximum All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

For the safety objective, considering a prevalence of ESAVI with the SPUTNIK V vaccine of 60% (17) with a precision of 5% for a confidence interval of 95%, a sample size of 369 patients was estimated.

For the effectiveness objective considering the publication of the published phase 1/2 results of the Sputnik V vaccine study (2) and assuming that the vaccinated population in Buenos Aires will have the same behavior as published, the following sample Adjusting for a 20% loss to follow-up and considering that the immunogenicity of these patients is lower than that of the general population, the calculation of the sample size was estimated at 100. A random effect fixed model was used to compare the immunoglobulin G levels for coronavirus type 2 that causes severe acute respiratory syndrome. A level of statistical significance less than 5% was considered. The analysis was carried out with software R version 4.0.3

The COVIDAR group provided the Serokits for sampling and the ELISA COVIDAR IgG kits, supported by FOCEM and Asoc. SAND. None of the funding sources provided economical support for the data collection, statistical analysis, or were used to write the manuscript, or to submit it for publication. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 25, 2021. ; Of the total ESAVI, the most frequent was pain at the injection site with both components of the vaccine, new or worse muscular pain and fever. All ESAVI were more frequent with the first componente except pain at the injection site, which was the same in both components and vomiting, that was more frequent with the second component. Figure 1 shows the frequency of ESAVI globally and after each component.

All rights reserved. No reuse allowed without permission. 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 The copyright holder for this this version posted October 25, 2021. ; preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 25, 2021. ; https://doi.org/10.1101/2021. 10.21.21265349 doi: medRxiv preprint In patients with COVID-19 prior to vaccination, antibodies at day 21 after the first component reached almost the highest levels compared to those patients who did not have COVID-19, and the rise between the last measures was lower than patients without COVID-19 (table3 and figure 3) . 

This study shows that Sputnik V COVID-19 vaccine in dialysis patients had a low rate of ESAVI and good immunogenicity. Regarding adverse events, none were characterized as a major event, the most frequent ESAVI was pain at the injection site with both components of the vaccine. Considering systemic symptoms, new or worse muscle pain and fever were the most frequent and none of the ESAVI required hospitalization. ESAVI were less frequent compared to phase 2 and 3 studies of the vaccine and also lower compared to the ESAVI in health workers (17) . This could be due to the widespread use of antipyretics prior to vaccination. Studies in dialysis patients with BNT162b2 mRNA COVID-19 vaccine showed that also local pain was the most frequent ESAVI in dialysis patients, and diarrhea, fatigue and myalgia among the sistemics (18, 19) . Symptoms were less frequent in the second component. We All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 25, 2021. ;  found that history of allergy, young age and history of transplantation were associated with a higher frequency of adverse events.

Regarding the seroconversion rate, almost 40% of the patients did not achieve a detectable anti-SARS-Cov-2 IgG antibody titer with the first component, but had a significant increase with the administration of the second component. Patients with COVID-19 prior to vaccination reached almost maximum levels of antibodies at 21 days of the first component, remaining stable at 21 days of the second. Almost 98% of our population had detectable antibodies after vaccination at that time. Hyporesponse to vaccines in general has been described in dialysis patients, in vaccination against hepatitis B, which shows a seroconversion of only 40-70% compared to more than 95% in healthy controls (20) , attributing associated factors such as age, the presence of diabetes, nutritional status and altered innate and adaptive immune response (21) . However, in our experience, the level of seroconversion with the two Sputnik V components was, on the contrary, much higher, and has already been described with other COVID-19 vaccines in dialysis patients (19, (21) (22) (23) (24) (25) (26) , thus highlighting the importance of a complete vaccination in this patients (19, 26) . Besides, patients who presented COVID-19 after the first Sputnik V component had mild forms of the disease, as has been seen in the general population (27).

Taking into account the group of patients who had detectable anti-SARS-Cov-2 IgG antibodies before the first dose, without a clinical history of COVID-19, thus considered asymptomatic patients, has been already described in the literature (15, 28) . This group of patients as well as those with known COVID-19 presented a significant seroconversion with the first component (19) , this is not reported in most of the other studies since these patients were generally excluded. The presence of SARS-Cov-2 infection was not associated with a higher frequency of ESAVI. Recent studies show that the majority of patients with COVID-19 prior to vaccination develop robust and durable immune responses at 6 months, with less than 5% no evidence of humoral and cellular immunity (29, 30) . However, preliminary studies carried out with another type of vaccine showed that in the case of those immunized without previous infection, there was a drop in antibody levels at six months, considering the need for a third dose (31, 32) . In this context, determining which subgroup of dialysis patients would need a booster dose according to their characteristics, comorbidities and type of vaccine received deserves to be investigated in the coming months. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Our work has the strength of being the first published report on the safety and efficacy of the Sputnik V vaccine in dialysis patients, especially considering that this vaccine

has not yet been recognized by the WHO. The weakness of this study was not being able to evaluate cellular immunity, two reports (18, 24) found a cellular immunity (T response) close to 60% of those vaccinated, less than humoral immunity found in our study which was almost 100%. In any case, the effectiveness of the vaccines implemented in dialysis patients will be demonstrated by the reduction in the infection rate as well as the fatality rate.

Dialysis patients constitute a vulnerable population for SARS-Cov-2 infection, beyond the recommendations that were implemented by dialysis units (33) , full vaccination is a priority and necessary. The Sputnik V vaccine has been shown to be safe and effective in this patient population.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 25, 2021. ; https://doi.org/10.1101/2021.10.21.21265349 doi: medRxiv preprint

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