The Fourth Dose of CoronaVac Vaccine Results in a Small Increase of Seroconversion and Antibody Values Among Kidney Transplant Recipients

Abstract

We recently reported that, after a homologous booster dose of CoronaVac vaccine, only 20.3% of 300 kidney transplant recipients who were seronegative before the third dose seroconverted.1 Similar evidence from other vaccine platforms2 and the link between seronegativity and breakthrough infections3 has prompted the transplant community to propose additional doses. Here, we describe the antibody responses and breakthrough infections after the fourth booster dose of homologous CoronaVac vaccine from our ongoing prospective, phase 4 study (NCT04801667). Adult kidney transplant recipients with no previous COVID-19 who received all 4 homologous doses of CoronaVac vaccine in the transplant center were enrolled. The fourth dose was administered between September and October 2021. Immunogenicity analysis was performed using Abbott Architect SARS-CoV-2 IgG II assay (lower limit of positivity 50 AU/mL) immediately before and at least 28 d after the booster. The occurrence of a new confirmed SARS-CoV-2 infection was registered between 15 and 150 d after the fourth dose. There were 871 vaccinated patients with the fourth dose in the center. No serious adverse event or acute rejection episodes occurred after vaccination. From them, 603 subjects had 2 laboratory evaluations before and after vaccination and were included for this analysis. Their median age was 51 (IQR 44–57) y, 56% were men, and 42% were in use of tacrolimus, prednisone, and mycophenolate. Before the fourth dose, 279 of 603 (46.2%) patients had a negative IgG-anti-SARS-CoV-2 serology. After a median of 35 (IQR 35–63) d, 18.9% of them seroconverted, with a median titer of 78 (IQR 61–189) AU/mL after the booster (Figure 1A), resulting in a final seroprevalence of 62.6%. The seroconversion rate among patients who received the fourth dose up to 8 wks was 22.2%, similar to that observed in those were vaccinated >8 wks apart from the third dose (17.2%, P = 0.332). Using the binary logistic regression model, investigating age, gender, diabetes mellitus, time from transplantation, deceased donor transplantation, and immunosuppression, older age and deceased donor transplantation were independent factors associated with lower likelihood of seroconversion after the fourth dose (Table S1, SDC, https://links.lww.com/TP/C463).FIGURE 1.: Comparative analysis of the IgG-anti-SARS-CoV-2 values before (rose points) and after (blue jade points) the fourth homologous vaccination. Abbott Architect SARS-CoV-2 IgG II immunoassay for total IgG antibodies against the receptor binding domain of the S1-subunit of the SARS-CoV-2 spike protein in logarithmic scale. The lowest limit of detection by the manufacturer is 6.8 AU/mL (0.83 log), and the analytical measuring interval is 21 (1.32 log, limit of quantification) to 40 000 (4.60 log) AU/mL. The threshold for considering the test as positive is 50 AU/mL or 1.69 log (dotted line). A, Antibody values of the 279/603 patients who initially had a negative IgG-anti-SARS-CoV-2 serology. Of them, 53 (18.9%) presented seroconversion (blue jade points above the dotted line, after the fourth dose), with a median titer of 78 (IQR, 61–189) AU/mL. The remaining 226 (34.7%) individuals persisted with no humoral response. B, The other 324/603 (53.8%) subjects were already seroprevalent before the fourth dose of the vaccine. The median titers increased from 517 (IQR, 173–1437) to 635 (IQR, 244–1454) AU/mL after the booster (P = 0.078). IgG, immunoglobulin G; IQR, interquartile range; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.In the 324 of 603 (53.8%) individuals who were already seropositive before the fourth dose, there was a nonsignificant increment of the median titers from 517 (IQR 173–1437) to 635 (IQR 244–1454) AU/mL after the booster (P = 0.078) (Figure 1B). Between days 15 and 150 after the booster dose, there were 115 confirmed cases of SARS-CoV-2 infection at a median time of 108 (IQR 94–130) d and 12 COVID-19-related deaths. From these, 113 patients acquired the infection after December 29, 2021—the period of the omicron predominance in Brazil. The COVID-19 incidence rates were similar between the seropositive versus seronegative patients (8.6 versus 7.8 cases/1000 patient-days, P = 0.514); however, the lethality rate from COVID-19 was significant higher in those patients without humoral response after vaccination (18.2% versus 3.3% in those seropositive, P = 0.009). Our results demonstrate that a fourth homologous dose of the inactivated virus CoronaVac vaccine produces a small increase in immunogenicity in terms of humoral response, which is similar to the findings reported by others about fourth doses of mRNA vaccines in transplant recipients.4,5 Older age and deceased donor transplantation, which actually may reflect a higher state of frailty of the recipient, were independent factors for poorer serological response. Limitations include the single-center nature, the absence of evaluation about cellular immunity, and the qualitative evaluations of the antibody neutralization. The concentration of COVID-19 cases after December 2021 and the similar attack rates between seroconverted and seronegative patients suggest the immune escape of omicron variant. The high percentage of patients remaining unresponsive after the fourth dose (37.4%) and the negative relationship between seroprevalence and deaths from breakthrough infections suggest the need for additional immunization alternatives and innovative preventive and protective strategies.

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