key: cord-0684778-1xuw2uph authors: Holt, Stephen Geoffrey; Mahmoud, Sally; Ahmed, Wasim; Acuna, Juan Manuel; Al Madani, Ayman Kamal; Eltantawy, Islam; Zaher, Walid Abbas; Goodier, Gareth John; Al Kaabi, Nawal Ahmed; Al Obaidli, Ali Abdulkareem title: An analysis of antibody responses and clinical sequalae of the Sinopharm HB02 COVID19 vaccine in dialysis patients in the United Arab Emirates date: 2021-10-05 journal: Nephrology (Carlton) DOI: 10.1111/nep.13980 sha: 9f717577656abeabd9d772d4cb5368a992d69eae doc_id: 684778 cord_uid: 1xuw2uph AIM: To establish the responses to the Sinopharm HB02 COVID‐19 vaccination in the dialysis population, which are not well established. We examined the humoral responses to the Sinopharm COVID vaccine in haemodialysis patients. METHODS: Standard vaccinations (two doses at interval of ~21 days) were given to all consenting haemodialysis patients on dialysis (n = 1296). We measured the antibody responses at 14–21 days after the second vaccine to define the development of anti‐spike antibodies >15 AU/ml after vaccination and observed the clinical effects of vaccination. RESULTS: Vaccination was very well tolerated with few side‐effects. In those who consented to antibody measurements, (n = 446) baseline sampling showed 77 had positive antibodies, yet received full vaccination without any apparent adverse events. Positive anti‐spike antibodies developed in 50% of the 270 baseline negative patients who had full sampling, compared with 78.1% in the general population. COVID infection continues to occur in both vaccinated and unvaccinated individuals, but in the whole group vaccination appears to have been associated with a reduction in the case fatality rate. CONCLUSION: The humoral immune responses to standard HB02 vaccination schedules are attenuated in a haemodialysis cohort, but likely the vaccine saves lives. We suggest that an enhanced HB02 vaccination course or antibody checking may be prudent to protect this vulnerable group of patients. We suggest a booster dose of this vaccine at 3 months should be given to all dialysis patients, on the grounds that it is well tolerated even in those with good antibody levels and there may be a survival advantage. In this analysis of humoral response to the Sinopharm COVID-19 vaccine in over 400 haemodialysis patients in United Arab Emirates, positive anti-spike antibodies (>15 AU/ml) developed in 50% of 270 COVID-19 sero-naive patients who had full sampling, compared with 78.1% in the general population. Side effects were remarkably few. The coronavirus (SARS-CoV-2), causing COVID-19 infection started to spread rapidly across the world in December 2019 and has caused an international clinical and public health emergency. The worldwide response to this pandemic has included the rapid development of vaccines. There are now several vaccines that are now approved by the WHO for emergency use across the globe including using standard technologies (e.g., inactivated virus or purified protein) and novel vaccine approaches (mRNA or adenovirus vectors). Although registered for human use in the United Arab Emirates (UAE) since September 2020, the Sinopharm vaccine trial results, have recently been reported and noted it efficacy to prevent symptomatic and hospitalized disease to be~78.1% for all age groups 1 without comorbidities. The prognosis for the elderly and those with chronic diseases is worse than for younger and healthier individuals, but of particular concern are those with chronic kidney disease (CKD), in whom the outcomes are much worse than for others affected with other chronic diseases. 2 In particular, the case fatality rate is much higher in dialysis patients, with mortality estimates for dialysis patients developing SARS-CoV-2 (COVID19) virus infection as high as 31%. 3 We reported previously a lower mortality 4 during the first wave of the virus in the Abu Dhabi. 4 Nevertheless, we were keen to vaccinate dialysis patients early and the Abu Dhabi Department of Health made trials available in July 2020 and made the Sinopharm HB02 vaccine freely available to any resident of the UAE in late 2020, and this early and aggressive vaccination campaign allowed the UAE to achieve internationally very high vaccination rates. No other vaccines were freely or widely available within the Emirate of Abu Dhabi during the antibody study period. Other groups with renal impairment, for example, after renal transplantation 5 and with advanced CKD 6 are also at high risk. 7 Many studies report infection in a high percentage of dialysis patients with COVID-19 (~19%, range of 10%-24%) among its dialysis centres. 8 The overall mortality of COVID-19 infection in a dialysis population reported at 14%-31%. [9] [10] [11] However, median ages in these studies was generally older than the UAE dialysis population. One study reported 66% of those who died were above the age of 75 years. 11 Despite screening, contact avoidance, distancing, isolation and droplet control precautions (through extensive use of PPE), patients with COVID-19 can infect others at any time, especially during transport to, and at haemodialysis centres during frequent close contact in dialysis units. This makes this highly comorbid population especially vulnerable. Thus, this infectious disease requires specific control measures to avoid community and family transmission in areas in and around renal units, that are now well described. 12 Vaccination in dialysis patients is generally less successful, and circulating antibody response less durable, in renal patients as exemplified by the increased dosing requirements and boosters for hepatitis B vacation. 13 Many studies have reported showing that standard COVID vaccination antibody response with the Pfizer/BioNTech, Astra-Zenica vaccine in haemodialysis (HD) patients was suboptimal but provides good antibody responses in a number of patients. 14 Yet there is little data on the efficacy of the Sinopharm vaccine, nor on its protective effects. This study set out to examine the antibody response to this vaccine in a HD cohort in Abu Dhabi, UAE. We have monitored all COVID19 infection since our first case in March 2020 and started vaccinating haemodialysis patients as soon as a vaccine became available in January 2021, and all patients were offered vaccination at our centre. We report a prospective, concurrent cohort study of antibody responses in patients undergoing consultation and haemodialysis at the SEHA Kidney Care which encompasses many facilities throughout Abu Dhabi, as well as describing the clinical events around the pandemic in this patient cohort. The epidemiological data on COVID infection is described from March 2020 to June 2021 but the antibody study ran from January 2021 to the current data and data was censored at the end of Research Ethics Committee (CVDC-ADHRTC-25 15 ). Patients were consented separately to receive the vaccine and to allow us to study the antibody response. The HB02 vaccine is an inactivated SARS-CoV-2 and is prepared by Two doses of HB02 vaccine were inoculated to the deltoid muscle of the upper arm according to the immunization schedule at day 0 (T0) and day 21 (T1) (±7 days). These were given on routine HD sessions, and without dialysis anticoagulation withdrawal. Subjects gave a blood sample at baseline before immunization (Baseline), before the second dose T2) and between 14 and 28 days after the second dose (T3). Samples were batched and assayed retrospectively or antibodies to the S1/S2 spike protein as well as a 'neutralizing' antibody response. were performed using Cobas SARS-CoV-2 test by Roche Diagnostics (Roche Molecular Systems, Branchburg, NJ, United States). COVID-19 IgG antibody testing was performed using the LIAISON ® SARS CoV-2 S1/S2 IgG assay (LIAISON ® XL Analyser, DiaSorin Inc.1951, USA) which uses a chemiluminescence immunoassay (CLIA) technology for the quantitative determination of anti-S1 and anti-S2 specific IgG antibodies to SARS-CoV-2 in human serum or plasma samples. Antibody titres <12 AU/ml were considered negative, 12-14.9 AU/ml equivocal, and ≥ 15 AU/ml positive as per the manufacturer's instructions. The lower limit of quantitation (LLoQ) was 3.8 AU/ml and upper limit of quantitation (ULoQ) 400 AU/ml. Samples above the ULoQ were dealt with by assigning them the value of the ULoQ. Neutralizing antibody testing was performed using cPass™ SARS-CoV-2 Neutralization antibody detection kit by GenScript USA, Inc, which is a blocking enzyme-linked immunosorbent assay intended for qualitative direct detection of total neutralizing antibodies to SARS-CoV-2 in human serum and K2-EDTA plasma and were reported a percentage, with a LLoQ of 1%. Neutralizing antibody levels >30% were considered positive, as per FDA recommendation. Both antibody detection kits are FDA approved and performance indicators have been verified and approved in Bioegnix laboratory for use on clinical samples. Spike Antibody results were expressed as AU/ml and neutralizing as %. Levels below the LLoQ were dealt with by assigning them the value of LLoQ/2 and those above the ULoQ were assigned the value of the ULoQ. 16 The antibody study flow, and data, are summarized graphically in Despite being given an intramuscular injection during the dialysis procedure and with standard dialysis anticoagulation, there were remarkably few side effects. Few patients experienced any side effects from the vaccination itself and no bleeding issues were noted. There was one recorded immediate moderate side-effect of pain in 1986 recorded administrations (<0.05%), and three more reported mild pain, as all patients given vaccination had immediate side effects recorded. One patient developed a moderately severe maculopapular rash, 6 days after vaccination. Overall mortality rates regardless of vaccination status was 36/511 cases (7%). From the start of the pandemic in our units (March showing a trend towards those who died being older if they were vaccinated (but p = ns) Figure 4 shows the survival curves to 60 days for vaccinated and unvaccinated patients who contracted COVID-19 (with Table S1 showing the numbers at risk). The censoring data for this data was June 22 2021 (so we have full 60 day mortality data available). Vaccination in dialysis groups is usually less efficacious than in the general population but a number of relatively small early studies from the mRNA and adenoviral vector vaccines (recently summarized by Carr et al. 19 ) have shown good seroconversion rates in dialysis cohorts from full vaccination of 71%-97%, 19 but little data on SinoPharm vaccine exists in this group. We have noted that the Sinopharm vaccination in dialysis patients was really very well tolerated when given on dialysis and there was no need to change the anticoagulation to give the dose on dialysis. We had only a single case of moderate side-effect attributed to the vaccine with a rash, and it was remarkable that most patients reported no immediate problems, to the point that anecdotally some patients even doubted that they had actually been given real vaccine. However, the seroconversion was lower than the general population (~78%) at~50% in the HD patients. The mortality rate in the entire HD group appears lower after vaccination, but the low numbers in both groups mean that statistical significance overall was difficult to demonstrate, but the death rate in the dialysis cohort generally low compared with reported cases elsewhere in the literature which has varied between~14% and 30% in unvaccinated individuals in early reports. 9, 10, 11 We previously reported the development of generally good antibody responses to COVID19 infection, before vaccination was available, in our dialysis cohort in the first wave. 4 However, we also noted a lack of antibodies in some patients, further increasing our anxiety around the effectiveness of the vaccination in this group of patients. Even though we reported an internationally low death rate before the vaccine was available it was still much higher than the general population, so we were anxious to protect this very vulnerable group from second and subsequent waves of COVID infection. The relatively low death rate is reported here, this may reflect a relatively lower age than many countries dialysis populations. We have shown that the COVID vaccine given at standard doses and dosing intervals is moderately successful in provoking a protective immune response with Anti-S antibodies in around half our patients (50%), but the antibody responses in many patients were suboptimal, and not demonstrated at all in some. The fact that HD patients have a less robust response to vaccination is not an unexpected result and it has recently been reported that patients who received the Pfizer vaccine in a much smaller cohort of HD patients, had a poor antibody response. 14 In the latter study 73% seroconverted using the Pfizer study in a much smaller cohort, but a summary of published seroconversion frequencies showed better seroconversion rates. 19 No data yet exists on mixing vaccine types or increasing the dose or dosing frequency for particular populations. It is also interesting to note that this vaccine was well tolerated even by those who already possessed good antibody levels, suggesting that augmented dosing of this vaccine may not be problematic. Our results may also suggest, since we have a relatively young dialysis population, that we might expect an even lower seroconversion rate in older populations to a standard vaccination regimen. Other vaccination associated antibody titres wane more rapidly in dialysis patients suggesting that vaccine induced immunity wanes quickly. However, based on these and other data we are now providing early booster doses to all patients with this vaccine. The fact that we have recently seen a rise in the number of vaccinated patients developing a positive COVID test may relate to new variants which may partially evade the antibody protection provided by the vaccine. 20 The strengths of this study were that it included a relatively large cohort of dialysis patients and had full antibody results at baseline, prior the first and second vaccine. We have also shown that vaccination appears to reduce the duration COVID PCR positivity to the second negative PCR ( Figure S3 ). similar, yet even if we assign a 70% positivity rate at the third sampling, this would make the overall seroconversion rate~56%, still well below the figure quoted for the general population. (see Figure S1A ,B). We also urge caution in the interpretation of the 'neutralization' assay which has been reported to have some sensitivity issues so caution should be applied in its interpretation and results should not be conflated with true microneutralisation assays. 21 Nevertheless, we are encouraged by case fatality reduction and the diverging mortality curves as well as the data suggesting that vaccination seemed to be effective at protecting younger patients and limiting the length of disease in survivors. However, we cannot exclude advances in our care being responsible for the improvement in mortality in later patients. Additionally, we cannot exclude the fact that the first and second waves of COVID infection may have left a more physiologically robust dialysis cohort. Most worryingly, we do not have information on the variants of SARS-Co-2 which may include a number that may be relatively resistant to vaccine directed antibodies and may explain the rise in COVID cases more recently among vaccinated patients ( Figure S2 ). Whilst COVID positive patients were generally PCR tested every other day whilst hospitalized, the frequency of testing at discharge was with dialysis sessions following discharge, and was generally performed on every session until two negatives were obtained (in order to help with isolation decisions). Although we showed that vaccination appeared to reduce the median time to COVID PCR negativity, we cannot exclude the possibility that this was related to differing testing intervals. This was especially true for those who remained PCR positive for some time and who were symptomatically well, where testing frequency may well have been reduced. Of course, PCR tests do not measure replicant competent virus, and we do expect infectivity to have reduced before PCR negativity, 22 so the clinical significance of this finding is uncertain but consistent with possible faster viral clearance. Testing for viral genotype is being considered to further clarify some of the more recent positive patients despite apparently good antibody levels antibody. The Sinopharm COVID HB02 vaccine given in standard doses on dialysis does induce antibody response in the haemodialysis population in around half of all subjects. Seroconversion, is not as good as in the general population (50% vs. 78%) but this was an expected result and this response does not appear to be as good as mRNA or adenovirus induced seroconversion, but this vaccine may be better tolerated. This has prompted us to intensifying the dosing schedule in these patients. Importantly vaccination does appear to offer some protection from death, as the case fatality rate has halved from community acquired infection since the vaccination roll out. Dialysis patients may have a requirement for an augmented standard vaccination schedule with this vaccine to provide more protection to this vulnerable group. 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The UAE government is acknowledged and thanked for providing rapid and continuous support for vaccination and treatment of COVID-19 infection to all residents of the UAE.Both SEHA Kidney Care and G42 provided in kind funding for this study -SKC provided clinical time, materials, nursing and medical expertise. G42 provided antibody testing and laboratory expertise. The authors declared no conflict of interest.