key: cord-0952886-srxp67q9 authors: Eren Sadioğlu, Rezzan; Demir, Erol; Evren, Ebru; Aktar, Merve; Şafak, Seda; Artan, Ayşe Serra; Meşe, Sevim; Ağaçfidan, Ali; Çınar, Güle; Önel, Mustafa; Karahan, Zeynep Ceren; Şengül, Şule; Keven, Kenan; Türkmen, Aydın title: Antibody response to two doses of inactivated SARS‐CoV‐2 vaccine (CoronaVac) in kidney transplant recipients date: 2021-10-17 journal: Transpl Infect Dis DOI: 10.1111/tid.13740 sha: 3ecb6f814d5213f71a351de696e5eb81fdc239c6 doc_id: 952886 cord_uid: srxp67q9 BACKGROUND: Coronavirus Disease‐19 (COVID‐19) has high mortality in kidney transplant recipients (KTR), and vaccination against severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) is vital for this population. Although the humoral response to messenger RNA vaccines was shown to be impaired in KTR, there is a lack of data regarding the antibody response to inactivated vaccines. We investigated the antibody response to two consequent doses of the inactivated SARS‐CoV‐2 vaccine (CoronaVac; Sinovac Biotech, China). METHODS: A total of 118 patients from two centers were included. The levels of anti‐SARS‐CoV‐2 immunoglobulin‐G antibodies against the nucleocapsid and spike antigens were determined with enzyme immunoassay (DIA.PRO; Milano, Italy) before the vaccine and one month after the second dose of the vaccine. Thirty‐three patients were excluded due to antibody positivity in the serum samples obtained before vaccination. RESULTS: Eighty‐five patients, 47 of whom were female, with a mean age of 46 ± 12, were included in the statistical analysis. The maintenance immunosuppressive therapy comprised tacrolimus (88.2%), mycophenolate (63.6%), and low‐dose steroids (95.3%) in the majority of the patients. After a median of 31 days following the second dose of the vaccine, only 16 (18.8%) patients developed an antibody response. The median (IQR) antibody level was 52.5 IU/ml (21.5–96). Age (48 vs. 38, p = .005) and serum creatinine levels (1.14 vs. 0.91, p = .04) were higher in non‐responders and were also found to be independently associated with the antibody response (odds ratio (OR): 0.93, p = 0.012 and 0.15, p = 0.045, respectively) in multivariate analysis. CONCLUSION: In this study, we found the antibody response to the inactivated vaccine to be considerably low (18.8%) in KTR. Increased age and impaired renal function were associated with worse antibody response. Based on the knowledge that mRNA vaccines yield better humoral responses, this special population might be considered for additional doses of mRNA vaccination. This two-center cross-sectional prospective observational study was conducted at the transplantation units of Ankara University School of Medicine and Istanbul University Istanbul School of Medicine between January 22, 2021, and June 21, 2021. This study was approved by the Ankara University School of Medicine Ethics Committee for Clinical Studies (Approval Number: I3-207-21). Written informed consents had been obtained from all patients before the blood samples were collected. Before vaccination, blood samples were drawn during regular control visits before the vaccination program was initiated for transplant recipients. After vaccination, blood samples were obtained from the same patients one month following their second vaccine shots. All blood samples were centrifugated at room temperature (23 • C), and the sera samples were kept at -80 • C until the tests were studied. Antibody Clinical and laboratory data are expressed as percentages, means A total of 373 patients' samples were collected before vaccination. However, due to an increase in COVID-19 case numbers and the partial lock-down periods during our study, most of the patients could not In total, out of 85 patients whose mean age was 46 ± 12 only 16 (18.8%) patients developed an antibody response to the inactivated SARS-CoV-2 vaccine 4 weeks following the second dose of the vaccine. There were 47 (55.3%) female patients and gender rates were not different among the patients who had a positive antibody response. The patients who had a positive antibody response were younger than the non-responders (Table 1 ). There was no difference regarding donor type, human leukocyte antigen mismatch, the time elapsed after transplantation, renal replacement therapy history, or renal replacement therapy duration between the two groups (Table 1) . Immunosuppressive therapy regimens including induction or maintenance therapy and F I G U R E 2 Median COVID-19 IgG levels after vaccination history of rejection or antirejection therapy were not different among the groups (Table 1) . Serum creatinine level, which was obtained when the postvaccination blood samples were collected, was lower in the antibody responder group than in the non-responder group (median, IQR: 0.91 mg/dl (0.62-1.27) vs. 1.14 mg/dl (0.92-1.36), p = .04). Unsurprisingly, the estimated glomerular filtration rate was higher in the antibody-positive group (93.3 ml/min/1.73m 2 (55-116) vs. 67.4 ml/min/1.73m 2 (53-81), p = .04). Proteinuria levels were not different between the two groups. Additionally, despite the missing data, the vaccination profile regarding influenza, pneumococcus, and Bacillus Calmette-Guerin was similar between the two groups, and the majority of the patients had had a Bacillus Calmette-Guerin vaccine (64.7%) ( Table 1) . Table 1) . The most common adverse events related to the vaccination were arthralgia, myalgia, and fatigue (7%) in the entire patient population. There was no allergic reaction or anaphylaxis. This study indicated that, in the KTR population, humoral response to inactivated SARS-CoV-2 vaccine was very low ( Immunosuppressed patients including KTR are known to have poor vaccine responses compared to a healthy population. 16 Seyahi et al., 15 in their study, showed that patients with immune-mediated diseases, especially the ones who were on immunosuppressive drugs and those aged ≥60 years, had less antibody response to CoronaVac vaccine than the healthy controls did. Bertrand et al. 14 12 reported a 54% antibody response to two doses of the mRNA vaccine, and they concluded that poor response was a concern in the patients who were on antimetabolite immunosuppression. In line with these findings, we found that a worsening graft function and advanced age were risk factors for a poor antibody response to the vaccine. Antiproliferative usage was also less frequent in antibody-positive patients in our study. However, this did not reach statistical significance, which was probably due to the limited number of cases. Kamar et al. 23 reported that the antibody response rate was 40% after the second dose, and increased to 68% after the third dose of the mRNA vaccine in KTR. Forty-four percent of the patients, who had been seronegative before the third dose, developed antibodies after the third dose. 23 It remains so far unknown what level of antibody titer would be preventive against SARS-CoV-2, but it was shown that dialysis patients had lower titers which peaked later than in normal controls, 25 and so did the KTR. 26, 27 Although these studies were conducted with the patients who had mRNA vaccines, we found that antibody titers were very low in our study. From an immunological point of view, it has been shown in adults that the previous vaccinations for influenza and/or pneumococcal disease do not hamper the specific immune response to SARS-CoV-2 BNT162b2 vaccination. 28 Here in the present study, we found similar findings with the inactivated SARS-CoV-2 vaccine. There were many limitations of our study. The sample size was small and, unfortunately, we had no control group to compare the antibody response to the inactivated vaccine. However, Tanriover et al. 10 reported the seropositivity rate as 89.7% in inactivated vaccine recipients of CoronaVac in the phase 3 trial in healthcare workers. Therefore, we might assume that, in the KTR population, the humoral vaccine response to the inactivated vaccine is weaker than in healthy individuals. There were difficulties in performing multivariate models due to the small sample size. We did not have the chance to study the neutralizing activity of the antibodies or to determine the cellular vaccine response. In conclusion, our study showed that the antibody response rate to two doses of the inactivated SARS-CoV-2 (CoronaVac) vaccine in KTR patients was very low (18.8%). Increased age and serum creatinine levels were associated with non-responsiveness to the vaccine. The third dose of the vaccine, especially that of mRNA vaccines or vaccines with adjuvants, should be strongly recommended to the transplant recipients. 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Vaccines (Basel) This study was funded by the Turkish Transplantation Immunology and Genetics Association (Transplantasyonİmmünolojisi ve Genetigi Dernegi). We would like to thank Bio. Burcu Uysal for her technical contribution to the study. The authors declare that they have no conflict of interest.