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NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx Revista de la Sociedad Española de Nefrología www.revistanefrologia.com Revision Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum Borja Quirogaa , María José Solerb,c,∗ , Alberto Ortizc,d,∗ , Patricia de Sequerac,e , on behalf of SENCOVAC collaborative network1 a IIS-La Princesa, Nephrology Department, Hospital Universitario de la Princesa, Madrid, Spain b Nephrology Department, Vall d’Hebrón University Hospital, Barcelona, Spain c RICORS2040 (Kidney Disease), Spain d IIS-Fundación Jiménez Diaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN, REDinREN, Instituto de Investigación Carlos III, Madrid, Spain e Nephrology Department, Hospital Universitario Infanta Leonor – Universidad Complutense de Madrid, Spain a r t i c l e i n f o a b s t r a c t Keywords: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has negatively impacted on SARS-CoV-2 patients of the whole CKD spectrum, causing high rates of morbi-mortality. SARS-CoV-2 COVID-19 vaccines opened a new era, but patients with CKD (including kidney transplant, hemodial- CKD ysis and peritoneal dialysis) were systematically excluded from pivotal clinical trials. The Hemodialysis Spanish Society of Nephrology promoted the multicentric national SENCOVAC study aimed Peritoneal dialysis at assessing immunological responses after vaccination in patients with CKD. During the Kidney transplant first year after vaccination, patients with non-dialysis CKD and those on hemodialysis and Anti-spike peritoneal dialysis presented good anti-Spike antibody responses to vaccination, especially Humoral response after receiving the third and fourth doses. However, kidney transplant recipients presented Vaccines suboptimal responses after any vaccination schedule (initial, third and fourth dose). Espe- cially worrisome is the situation of a patients with a persistently negative humoral response that do not seroconvert after boosters. In this regard, monoclonal antibodies targeting SARS- CoV-2 have been approved for high-risk patients, although they may become obsolete as the viral genome evolves. The present report reviews the current status of SARS-CoV-2 vaccination in the CKD spectrum with emphasis on lessons learned from the SENCOVAC study. Predictors of humoral response, including vaccination schedules and types of vac- cines, as well as the integration of vaccines, monoclonal antibodies and antiviral agents are discussed. © 2022 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Nefrologı́a. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). ∗ Corresponding authors. E-mail addresses: mjsoler01@gmail.com (M.J. Soler), aortiz@fjd.es (A. Ortiz). @PepaSolerR. 1 SENCOVAC collaborative network (Appendix 1). https://doi.org/10.1016/j.nefro.2022.12.006 0211-6995/© 2022 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Nefrologı́a. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS 2 n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx Lecciones aprendidas del SENCOVAC: estudio prospectivo que evalúa la respuesta a la vacunación frente a SARS-CoV-2 en los pacientes con enfermedad renal crónica r e s u m e n Palabras clave: Síndrome agudo respiratorio severo coronavirus 2 (SARS-CoV-2) ha impactado negativa- SARS-CoV-2 mente en todos los pacientes con enfermedad renal crónica (ERC), causando elevadas tasas COVID-19 de morbimortalidad. La vacunación frente a SARS-CoV-2 han abierto una nueva era, aunque ERC precisamente los pacientes con ERC (incluyendo los portadores de un injerto renal y aquellos Hemodiálisis en programas de hemodiálisis y diálisis peritoneal) han sido sistemáticamente excluidos de Diálisis peritoneal los ensayos clínicos. La Sociedad Española de Nefrología (S.E.N.) promovió el estudio mul- Trasplante renal ticéntrico SENCOVAC para evaluar la respuesta inmunológica tras la vacunación en todo Anti-Spike el espectro de la ERC. Un año después de haber recibido la pauta inicial de vacunación, Respuesta humoral los pacientes con ERC sin necesidad de diálisis, y aquellos en hemodiálisis y diálisis peri- Vacunas toneal, han presenado una adecuada respuesta humoral (monitorizada con el desarrollo de anticuerpos frente a la proteína Spike), especialmente después de recibir la tercera y la cuarta dosis. Sin embargo, los portadores de un injerto renal han presentado una constante respuesta subóptima en cualquier momento de la vacunación (dosis inicial, tercera y cuarta dosis). Especialmente preocupante es la situación de los pacientes con respuesta humoral persistentemente negativa que no seroconvierten incluso ni tras recibir las dosis de recuerdo o boosters. En ese contexto, el manejo probablemente pasa por el uso de anticuerpos mono- clonales dirigidos frente a SARS-CoV-2 que han sido recientemente aprobados, asumiendo que pueden perder efectividad con el cambio del genoma viral. La presente revision tiene por objeto resumir y analizar la situación actual de la vacunación frente a SARS-CoV-2 en el espectro de la ERC enfatizando en los resultados del estudio SENCOVAC. Asimismo, a lo largo de la revisión se discuten los predictores de la respuesta a las diferentes dosis y tipos de vacunas y la integración de estas con los anticuerpos monoclonales y los agentes antivirales. © 2022 Publicado por Elsevier España, S.L.U. en nombre de Sociedad Española de Nefrologı́a. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http:// creativecommons.org/licenses/by-nc-nd/4.0/). COVID-19 death.8 OpenSAFELY analyzed data from 17,278,392 COVID-19 in the CKD spectrum adults and 10,926 COVID19-related deaths in England. In a fully adjusted model, patients cared for by nephrologists, Chronic kidney disease (CKD) is one of the fastest growing such as dialysis patients (Adj HR 3.69), transplant recipi- causes of death, projected to become the fifth global cause ents (Adj HR 3.55) and CKD (Adj HR 2.52 for patients with of death by 2040 and the second cause of death in countries eGFR < 30 ml/min/1.73 m2 , GFR category G4-5) patients were with long life expectancy before the end of the century.1,2 among the top 4 risk categories (Fig. 1B).8 However, within the While the increased risk of cardiovascular disease has received dialysis/transplant populations (kidney replacement therapy, most attention,3 persons with CKD are at increased risk of KRT), the additional risk associated to classical risk factors dif- death from non-cardiovascular causes and indeed the abso- fers from the general population. Thus, male sex or coexistent lute increase in the risk of death from non-cardiovascular diabetes, hypertension, coronary artery disease or lung dis- causes, including infection, is larger than for cardiovascular ease do not further increase the risk of COVID-19 death,9 causes, especially in the elderly.4 contrary to observations in persons not on KRT.8 Furthermore, Severe acute respiratory syndrome coronavirus 2 (SARS- the adverse impact of older age is smaller in persons on KRT: CoV-2) causes Coronavirus disease 2019 (COVID-19), a older KRT patients have a ∼4-fold increase in risk vs those condition of variable severity that may result in death. Ini- in their fifties, as opposed to a ∼15-fold increase in the tial reports of COVID-19 indicated that 20% of hospitalized general population.6 In the early pandemic waves in the most patients had diabetes mellitus (DM), 15% hypertension and affected countries or cities, such as Madrid, a 30% mortality 15% had cardiovascular disease (CVD), but CKD was not was reported in dialysis patients.10 This soon decreased to mentioned5 and was not considered a risk factor for many 13–16%, as it became apparent that, as for other populations, months. It is now clearly established that CKD is the main risk there was also a high prevalence of asymptomatic COVID-19 factor for severe COVID-19.6 According to the Global Burden among hemodialysis (HD) patients.11,12 Despite this, mortality of Disease (GBD) collaboration, CKD is the most prevalent risk remained above that of the general population and had a factor for severe COVID-19 worldwide7 (Fig. 1A). Additionally, dramatic impact on the epidemiology of KRT. As an example, CKD is the coexistent condition that most increased the risk of in Madrid in 2020, KRT incidence decreased 12% versus 2019 Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx 3 Fig. 1 – Global prevalence of CKD and impact of CKD on COVID-19 mortality. (A) Global prevalence of CKD by age according to Global Burden of Disease (GBD) data. Gray lines represent individual countries. (B) According to these data, CKD accounts for the increased risk of severe COVID-19 in 5.1% of the global population, or 23% of the global population at increased risk of severe COVID-19, as represented in panel B, being the highest contributor to global risk. Data for (A) and (B) from Ref. 7. (C) Risk of COVID-19 death for selected preexistent conditions from Ref 8. Dialysis and transplantation were the conditions that most increased the risk of death from COVID-19 in the OpenSAFELY study. Additionally, the increased risk conveyed by CKD G4/G5 was still higher than that conveyed by several of the often-cited risk factors for severe CVOD-19, including diabetes, chronic heart disease and hypertension. Even CKD G3 conveyed a higher risk of COVID-19 death than heart disease or hypertension. The discontinuous horizontal blue line indicates neutral risk (Adj HR = 1.0). while KRT prevalence decreased (−1.75%) for the first time since records began. COVID-19 was the most common cause SENCOVAC study: rationale and design of death in 2020 (33% of all deaths) and singlehandedly increased the annual mortality of KRT patients to 10.2% (34% The development of SARS-CoV-2 vaccines opened a new era in higher than the mean for 2008–2019), more so in kidney the COVID-19 pandemic. Phase III pivotal studies for assess- transplant recipients (+68%). However, the bulk of COVID-19 ing safety and efficacy of the different vaccines demonstrated deaths (209/285, 73%) occurred during the first COVID-19 protection against severe COVID-19.19–22 Indeed, vaccination wave, which roughly accounted for all the excess mortality was associated to lower rates of admissions and complications of KRT patients in 2020. This temporal pattern of COVID-19 derived from SARS-CoV-2 infections, including mortality, for mortality, despite further larger COVID-19 waves observed at least 5 months after the initial schedule.23,24 However, and before vaccines became available, suggests that appropri- beyond the pivotal clinical trials, a very low number of patients ate healthcare may improve COVID-19 outcomes in KRT included in prospective studies presented CKD at baseline.25 patients.13,14 With this background, we designed the SENCOVAC study Several factors may account for the high impact of COVID- with the aim of evaluating humoral response to SARS-CoV- 19 on KRT patients, especially during the first wave. Some 2 vaccines in the CKD spectrum (i.e. patients with advanced of them may have been transient, thus contributing to the CKD [eGFR < 30 ml/min/1.73 m2 , peritoneal dialysis [PD], HD severe impact of the first COVID-19 wave while others may and KT recipients).26 This real-world study had a prospective be permanent, accounting for a persistent increased risk of and observational design and included more than fifty cen- severe COVID-19. Thus, HD patients were unable to shield, ters in Spain. Inclusion and exclusion criteria are summarized as they had to travel to dialysis facilities thrice weekly. In in Fig. 2. At baseline, investigators collected epidemiological Spain this entailed shared vehicles with other patients at data, comorbidities, long-term treatments, and data specific a time when health authorities were actively suppressing for each cohort (Kt/Vurea, dialysis vintage, technique and masking.15,16 In this regard, shared transport emerged as a vascular access for HD and PD patients; immunosuppressive key risk factor for COVID-19.17 Moreover, at a time of severe therapy for KT; eGFR for ND-CKD and KT recipients). constraints in access to ICU care, KRT patients may have been Following the study protocol, at baseline, 28 days, 3 considered to have too low chances of survival, in a self- months, 6 months, and 12 months after completing the ini- fulfilling prophecy. Finally, early therapy for COVID-19 was not tial vaccine schedule, serum samples were obtained and sent evidence-based, and some of the useless medication combi- to a central laboratory to determine anti-Spike antibodies nations used may have increased the risk of fatal arrhythmia (Fig. 3). All samples were tested by a CE-marked commer- associated with long QT in dialysis patients.18 Among more cial method, a quantitative chemiluminescence immunoassay permanent factors, we find the spontaneous immune sup- (CLIA, Covid-19 Spike Quantitative Virclia® IgG Monotest, pression of uremia, the immunosuppressants prescribed to Vircell SL, Spain), with a sensitivity and specificity of 96% kidney transplant (KT) recipients and the high prevalence of and 100% respectively that detects IgG antibodies against the frailty among KRT patients. SARS-CoV-2 Spike protein. This assay was calibrated against Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS 4 n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx Fig. 2 – Design of the SENCOVAC study. Abbreviations: CKD: chronic kidney disease, CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration, eGFR: estimated glomerular filtration rate, HD: hemodialysis, PD: peritoneal dialysis, KT: kidney transplant. the First WHO International Standard for anti-SARS-CoV-2 the third dose and after the fourth dose. Since the timing of human immunoglobulin (NIBSC code: 20/136) and results were sampling was pre-specified, at each time point patients that expressed as IU/ml. According to the performance studies had received boosters could be compared with those who had of the manufacturer, based on the analysis of prepandemic not yet received the booster. serum samples, values ≤32 IU/ml were considered as negative, between 32 and 36 IU/ml as equivocal and values >36 IU/ml as positive, reflecting the presence of anti-Spike IgG antibodies Initial vaccination schedule response as a consequence of either previous infection or vaccination. SARS-CoV-2 vaccination in patients of the CKD spectrum was Investigators included an addendum to perform an interim safe, with a high incidence of adverse events (>50%) but all analysis at 9 months only in patients on HD.27 of them not serious (i.e., local pain, general discomfort, asthe- During the study, some patients received a third and a nia). The second dose (in patients with a two-dose scheme, i.e., fourth dose of vaccine. Although initial vaccination was based BNT162b2, mRNA-1273, ChAdOx1-S) generated more adverse on BNT162b2 (Pfizer-BioNTech® ), mRNA-1273 (Moderna® ), events than the first one. Factors associated to local and ChAdOx1-S (AstraZeneca® ) or Ad26.COV.2 (Janssen® ) vac- systemic reactions included previous COVID-19 (before vac- cines, subsequent boosters consisted of mRNA-based vaccines cination), being younger or a KT recipient.26 (BNT162b2 and mRNA-1273) (Fig. 3). Vaccination schedules After completing the initial vaccination schedule, patients were determined by the local public health authorities and with CKD presented disparities in their humoral response. The investigators did not intervene in vaccine prescription. first interim analysis of SENCOVAC included 1746 patients and The primary objective of the study was to determine analyzed humoral response 28 days after vaccination in 301 the humoral response after SARS-CoV-2 vaccination participants (28 non-dialysis CKD patients, 43 KT recipients, (initial and boosters) in patients with advance CKD 52 PD and 178 HD patients).26 Anti-Spike antibodies were posi- (GFR < 30 ml/min/1.73 m2 , HD, DP and KT recipients). tive in 95% of the patients (Fig. 4). However, a negative humoral Secondary objectives included safety, quantification of response was detected in 21% of the KT recipients, show- anti-Spike antibodies after vaccination, predictors of humoral ing that this population developed suboptimal responses and responses and establishment of cut-off anti-Spike antibody should be considered at very high-risk of SARS-CoV-2 infec- titers for protection against severe breakthrough infections. tions and of complications due to SARS-CoV-2.26 Beyond the risk of KT recipients for a suboptimal humoral response, the Safety and humoral response after SARS-CoV-2 type of vaccine was also an independent predictor for humoral vaccination response. Specifically, the BNT162b2 (30 ␮cg) vaccine was asso- ciated to 6-fold risk for negative humoral response than The safety and humoral response after SARS-CoV-2 vaccina- mRNA-1273 (100 ␮cg), probably due to the different amount tion were evaluated after the initial vaccination schedule, after of vaccine in each dose. Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx 5 Fig. 3 – Flow chart of the different humoral response assessment in SENCOVAC. Abbreviations: ND-CKD: non-dialysis chronic kidney disease, HD: hemodialysis, PD: peritoneal dialysis, KT: kidney transplant. These results agree with other studies recently summa- Third dose response rized by Ma BM et al. in a meta-analysis.28 Beyond the The suboptimal immunization after the initial vaccination lower rates of positive humoral response after initial vac- schedule was of special importance in vulnerable popula- cination of KT recipients compared to other patients with tions, including patients with CKD. Loss of acquired humoral CKD, all the CKD spectrum developed suboptimal humoral response was a key point during the pandemic as anti- responses when compared to healthy controls.28,29 The inher- Spike antibody titers correlated to efficacy.36 In the CKD ent immunosuppressive state of patients with CKD and spectrum, 25% of patients had fully lost their immunity specific features of dialysis and KT (immunosuppression, at 3 months with the majority of them presenting signifi- comorbidities) could explain why these cohorts are not fully cant declines in anti-Spike antibody titers.37 Within the CKD protected after vaccination.30 spectrum, KT recipients achieved the higher rates of lost The majority of published studies assessing the humoral humoral responses, with more than 50% of the fully vac- response to SARS-CoV-2 vaccines in CKD have been based cinated patients having undetectable antibodies (Fig. 4).38 on mRNA vaccines.31 Small reports on vaccines based on This waning dynamic was more pronounced at 6 months other technologies (such as inactivated virus or viral vec- and affected all the CKD spectrum. This situation opened tors) demonstrated a minimal disadvantage of these vaccines a new scenario: when to administer a new dose of SARS- compared to mRNA-based vaccines in the immediate serocon- CoV-2 vaccine.39,40 However, not all patients shared the same version in CKD (especially in KT) patients.32–34 On the other temporal pattern of the humoral immune response. Some hand, and although heterologous regimens (i.e., the use of dif- factors predicted the loss of anti-Spike antibodies such as ferent types of vaccines) as initial regimens had been poorly being a KT recipient, previous lower anti-Spike antibody titers explored, at least one study showed their efficacy in enhancing (due to suboptimal response to vaccination or lack of prior humoral responses over homologous regimens in HD.35 SARS-CoV-2 infection) or the type of vaccine.38,39,41 With this Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS 6 n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx Fig. 4 – Positive humoral response in each assessment of the SENCOVAC study across all the categories of the CKD spectrum from ref 26,27,38,42,55, 59. Positive immune response was defined as anti-Spike antibody titers above 36 IU/ml as positive, while ≤32 IU/ml were considered as negative, and between 32 and 36 IU/ml as equivocal, based on the manufacturer evaluation of serum from exposed and non-exposed individuals. Abbreviations: ND-CKD: non-dialysis chronic kidney disease, HD: hemodialysis, PD: peritoneal dialysis, KT: kidney transplant. background, Spanish health authorities (and other govern- patients at high risk for low humoral response. A recently ments worldwide) decided to administrate an early booster published clinical trial assessed the efficacy of a heterologous dose of mRNA-vaccines, prioritizing vulnerable cohorts (such regimen (ChAdOx1 nCoV-19) vs an mRNA booster (BNT162b2 as CKD patients) and irrespective of the humoral situation. or mRNA-1273) in immunosuppressed patients who failed The 6-month assessment of SENCOVAC included patients to respond to the initial schedule. This study demonstrated who had received 2 or 3 SARS-CoV-2 vaccine doses and allowed the beneficial effect of a homologous mRNA-based regimen.49 to evaluate the response to the third dose in CKD patients42 By contrast, a randomized clinical trial involving KT recipi- (Fig. 3). The administration of mRNA-based third doses sero- ents with negative humoral response after initial vaccination, converted 69% of the previous negative patients. By groups, demonstrated non-inferiority of a mRNA-based third dose vs receiving the third dose was associated to higher proportion a vector-based heterologous vaccination strategy.50 of positive humoral response (in comparison to 2 doses) in KT recipients (80% vs. 53%), patients on PD (100% vs. 71%), Fourth dose response patients on HD (96% vs. 64%) and patients with ND-CKD (97% Although anti-Spike antibody titers decreased over time, there vs. 73%) (Fig. 4).42 According to these results and in agree- is scarce information of the fourth dose effect in patients with ment to other published studies, KT recipients remained as CKD.51 Published studies have focused their attention to KT the low-protected cohort even after three vaccine doses.43 recipients, where a fourth dose improves humoral responses, In addition to the impaired immunity of KT recipients, the and should be primarily offered to prior non-responders.52–54 emergence of new SARS-CoV-2 variants may have influenced In this regard, SENCOVAC showed that in KT recipients the the capacity of vaccines to elicit anti-SARS-CoV-2 neutralizing fourth vaccine dose did not significantly increase anti-Spike antibodies. Al Jurdi et al. conducted a small but elegant study antibodies titers (Fig. 4). More worrisome was the low rate of in KT recipients that compared the neutralizing effect across seroconversion achieved in previously negative KT recipients different SARS-CoV-2 variants. They concluded that the third after this new booster, raising important concerns over the dose of SARS-CoV-2 mRNA vaccines presented lower effec- optimal strategy for persistently negative patients.55 In other tivity against new SARS-CoV-2 variants (i.e., Omicron) than CKD cohorts, a humoral response was observed and anti- against the original virus.44 Spike antibody titers increased after the fourth dose.55,56 In In contrast to the results in KT recipients, a robust humoral fact, among non-KT recipients, after the third dose, the preva- response was developed by the vast majority (more than lence of a negative humoral response was very low (<5%).55 95%) of non-KT recipients that had received the booster.42,45 Beyond booster administration and prior response to vacci- Although patients with CKD usually received mRNA-based nation, steroids and mycophenolate mofetil prescription was vaccines, some studies explored heterologous regimens with associated to low response to a fourth vaccine dose in KT.55,56 controversial results. Despite the use of mixed vaccine Similarly, suboptimal responses to SARS-CoV-2 vaccines were types, altogether studies revealed a humoral benefit with observed in other immunosuppressed populations.57,58 How- heterologous regimens46–48 constituting an alternative for ever, whether anti-Spike antibody titers represent the best Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx 7 readout to evaluate an optimal humoral response is unclear this was concordant with better humoral immune response and to our knowledge an optimal antibody titer threshold that to SARS-CoV-2 vaccine.68 avoids severe COVID-19 or complications has not yet been In Spain, specifically activated T cells were observed in identified. Until now, all patients with CKD have been eligible 46 of 69 (62%) HD patients.69 In France, the ROMANOV study for a full immunization against SARS-CoV-2 with four doses, tested anti-spike receptor binding domain (RBD) IgG and inter- but the optimal moment for further re-boostering needs to be feron gamma-producing CD4+ and CD8+ specific-T cells in the established.59 circulation 10–14 days after the second dose of BNT162b2 vac- A recent report from the general population in Israel dis- cine in 106 HD patients. The majority of patients (72/80, 90%) closed that a fourth dose results in a transient increase in generated at least one type of immune effector response, how- anti-Spike antibody titers and in increased protection from ever their response was lower and incomplete as compared to breakthrough COVID-19 for less than three months.60 This healthy controls. HD and immunosuppressive therapy were suggest that every effort should be made to time booster doses identified as risk factors for the absence of anti-spike CD8+ just before COVID-19 waves. T cells. Interestingly, previous history of COVID-19 in HD patients correlated with the generation of anti-spike CD8+ T Breakthrough SARS-CoV-2 infections cells at levels similar to healthy controls. The authors con- Protection against severe SARS-CoV-2 infections following cluded that HD patients might benefit from a third vaccine vaccination was demonstrated by pivotal clinical trials. The dose before transplantation.70 In concordance, the interferon- severity of COVID-19 substantially decreased after complet- ␥ release assay was suboptimal in KT recipients (8% positive ing the initial vaccination schedule.61–63 However, vaccination after the first dose and 30% after the second one). In addi- did not reduce to zero the risk of COVID-19 complications tion, the kinetics of Spike-reactive CD4+ T helper cells was and mortality still remained high, especially in KT recipi- delayed in KT recipients. The same pattern, but with a milder ents, despite new SARS-CoV-2 variants that appear be less defect than in KT recipients, was observed in a large PD lethal, at least in populations with a high degree of expo- cohort (n = 1256).30 In agreement with these results, Inter- sure to SARS-CoV-2 infection and vaccines, the availability feron Gamma Release Assay (IGRA) demonstrated a positive of booster doses and increased access to intensive care unit cellular response in 96.9% of controls, 89.3% of PD, 77.6% of care.64 Data of the last SENCOVAC report shows that probably HD, 61.3% of KT patients transplanted more than 12 months patients with CKD should benefit from establishing a higher ago and only 36% of those transplanted within the previous cut-off of anti-Spike antibody titers to ensure their protection, 12 months. These results suggest that recent transplant at least against COVID-19 requiring admissions.55 Indeed, we patients with the high immunosuppressive therapy are at know that the optimal vaccination strategy should consider higher risk for severe COVID-19.71 Interestingly, although the the infection background, comorbidities, immunosuppressive third dose of the BNT162b2 vaccine in KT recipients did drugs and the amount of received vaccine (number of doses not improve seroconversion, which remained under 50%, it and type). Luckily, the pandemic is evolving, and we are now increased the Spike-specific T cell response.72 RBD-specific facing the same pathogen but with a different costume. memory B cells were detected at similar proportions in virus- naïve patients on dialysis and vaccinated controls after two Cellular response after SARS-CoV-2 vaccination doses. However, in SARS-CoV-2-recovered patients on dialy- sis, anti-RBD memory B cells were unchanged after the third Cellular responses to SARS-CoV-2 vaccination were altered in dose.73 patients with kidney failure, including HD patients and, as In lymph nodes, KT recipients had deeply blunted expected, more pronouncedly in KT recipients.65,66 Sattler A SARS-CoV-2-specific germinal center B cell responses when et al. characterized cellular response to BNT162b2 prime-boost compared to healthy controls, coupled with severely hin- vaccination in KT recipients and HD patients. The preva- dered T follicular helper cells, SARS-CoV-2 receptor binding lence of spike-specific CD4+ T cell responses was similar in domain-specific memory B cells, and neutralizing antibody all studied groups (healthy controls, KT and HD patients). responses.74 However, the magnitude of the response was lower in KT recipients than in controls, as assessed by the frequency of Present and future of SARS-CoV-2 infection management CD154+ CD137+ Th cells.66 In addition, the prevalence of spike- specific CD8 responses was lower KT recipients: 5.13% (2/39) SARS-CoV-2 has not disappeared and probably will never KT responders vs less than half of responders in control and do. Thus, the updating of vaccines following viral mutations HD patients. Furthermore, there was a significant decrease in and periodic booster doses will be necessary, at least for the CD45RO+ CD26L− effector memory-like phenotype in KT high risk populations, following protocols that are well estab- recipients and HD patients.66 lished for influenza. This is currently being done with booster In the same line, following the second SARS-CoV2 vaccine doses, which are bivalent mRNA vaccines (BNT162b2, mRNA- dose, an anti-Spike T cell-specific response was observed in 1273),75,76 because they immunize against 2 strains of the 51% of KT recipients and in 100% of HD patients. The number virus, the original strain and the omicron variant, thus offer- of anti-Spike specific T-cells was similar to that found in ing greater protection against the virus that is currently in health care workers. Belatacept-treated patients displayed circulation. the worst response, developing only a few specific T cells.67 However, while vaccines decrease the risk of severe By contrast, patients treated with mTOR inhibitors had higher COVID-19 in the general population, KT recipients, as specific T cell–derived IFN␥ release than those without and SENCOVAC26,27,38,42,55,59 has shown, and other immunocom- Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS 8 n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx promised patients remain at higher risk for breakthrough established in CKD, stratification of the risk for COVID-19 severe infection and persistent viral replication.77 Novel SARS- complications should be based on comorbidities, prescribed CoV-2 could become a problem in well-vaccinated populations treatments and humoral response to prior vaccination. like in Spain. Some authors warn that measuring antibody levels with standard assays that currently use an ancestral spike antigen does not inform on protection.78 Other ques- Funding tions pending to be answered are the number and frequency of SARS-CoV-2 vaccine doses in the general population and in The present project has been supported by Diaverum, Vifor immunocompromised people, whether the amount on mRNA Pharma, Vircell, Fundación Renal Iñigo Álvarez de Toledo in the vaccine should be higher in immunosuppressed indi- and Instituto de Salud Carlos III (ISCIII) RICORS program viduals as is for hepatitis virus B, and whether the SARS-CV-2 to RICORS2040 (RD21/0005/0001) funded by European Union vaccine will be permanently included in the annual vaccina- – NextGenerationEU, Mecanismo para la Recuperación y la tion schedule like the flu. Resiliencia (MRR), FEDER funds. Other protective measures recommended for immuno- compromised persons,79 including prophylactic, early access Conflict of interest to and use of antivirals, and nonpharmaceutical interventions, such as the use of well-fitting masks or respirators, should also B. Quiroga has received honoraria for conferences, consult- be considered. ing fees and advisory boards from Vifor-Pharma, Astellas, Neutralizing Human monoclonal antibodies (mAbs) Amgen, Bial, Ferrer, Novartis, AstraZeneca, Sandoz, Labora- against SARS-CoV-2 is a promising and attractive approach torios Bial, Esteve, Sanofi-Genzyme, Otsuka. MJ. Soler reports for rapid prophylactic and treatment settings. However, some honorarium for conferences, consulting fees and advisory of these antibodies have already been deemed obsolete and boards from Astra Zeneca, NovoNordsik, Esteve, Vifor, Bayer, are no longer used since they identify epitopes that have Mundipharma, Ingelheim Lilly, Jansen, ICU Medical, and evolved as a consequence of mutations, and they no longer Boehringer. A. Ortiz has received consultancy or speaker recognize the most recent SARS-CoV-2 variants. The FDA fees or travel support from Astellas, Astrazeneca, Ami- has currently issued emergency use authorizations for eight cus, Amgen, Fresenius Medical Care, Bayer, Sanofi-Genzyme, anti-SARS-CoV-2 monoclonal antibody products. Cilgavimad Menarini, Kyowa Kirin, Alexion, Otsuka and Vifor Fresenius and tixagevimad may be used for pre-exposure prophylaxis, Medical Care Renal Pharma and is Director of the Cate- treatment or in situations where vaccines are less effec- dra Mundipharma-UAM of diabetic kidney disease and the tive, such as in immunocompromised individuals. Indeed, Catedra Astrazeneca-UAM of chronic kidney disease and elec- there is evidence on the use of tixagevimab/cilgavimab in trolytes. P. de Sequera reports honorarium for conferences, pre-exposure prophylaxis in both immunocompromised consulting fees and advisory boards from Amgen, Astellas, patients79 and specifically in transplant recipients.80–82 Astra Zeneca, Baxter, Braun, Fresenius Medical Care, Glaxo- Due to the potential of newly emerging SARS-CoV-2 vari- SmithKline, Nipro, Otsuka, Sandoz, Nipro, Vifor-Pharma. She ants in the future, vaccines and anti-SARS-CoV-2 mAbs will is the present president of the Spanish Society of Nephrology need to be constantly reassessed for their efficacy. Current (S.E.N.). data indicate that tixagevimab/cilgavimab neutralize Omicron BA.2 and BA.2.12.1, but this effect may be attenuated for BA.4 and BA.5.83–86 Antiviral agents, such as nirmatrelvir–ritonavir (Paxlovid) Key messages or remdesivir, are also in clinical use. However, despite being indicated in high-risk groups, including kidney • Patients of the CKD spectrum present an increased risk transplantation and CKD patients with additional comor- for COVID-19 complications and death. bidities, they cannot be administered to patients with • Patients on dialysis and, especially, kidney transplant eGFR < 30 ml/min/1.73 m2 .87 recipient develop suboptimal responses to initial vac- cination and booster doses. • Impaired humoral and cellular responses differ across Conclusions the CKD spectrum. Predictors of humoral response include previous response to vaccination, number of Vaccination against SARS-CoV-2, availability of health care vaccine doses, background immunosuppression and, resources, advances in treatment and the evolving virus have in some analyses type of vaccine. changed the impact of COVID-19 on patients with CKD. Initial • Future directions to protect patients with CKD include vaccination and booster doses generate suboptimal humoral the administration of new boosters with efficacy and cellular responses in patients with CKD, especially in KT against currently spreading SARS-CoV-2 variants, the recipients. Future strategies should include the administra- use of neutralizing anti-SARS-CoV-2 monoclonal anti- tion of updated vaccines (for emerging SARS-CoV-2 variants) bodies and of antiviral agents that can be prescribed in combination with the use of neutralizing human mono- to this population. clonal antibodies for high-risk patients and effective antiviral agents that can be prescribed to patients with advanced CKD. Although the protective titer of antibodies has not been Please cite this article in press as: Quiroga B, et al. Lessons from SENCOVAC: A prospective study evaluating the response to SARS-CoV-2 vaccination in the CKD spectrum. Nefrologia. 2023. https://doi.org/10.1016/j.nefro.2022.12.006 NEFRO-1123; No. of Pages 12 ARTICLE IN PRESS n e f r o l o g i a 2 0 2 3;x x x(x x):xxx–xxx 9 serological features of COVID-19 in urban hemodialysis Acknowledgments patients. J Clin Med. 2020;9:E2264, http://dx.doi.org/10.3390/jcm9072264. 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