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Homologous Third Dose of Inactivated Whole-virion Vaccine Fails to Elicit a Robust Immune Response Among Kidney Seronegative Transplant Recipients

Medina-Pestana, José PhD1; Covas, Dimas Tadeu PhD2,3; Viana, Laila Almeida MD1; Dreige, Yasmim Cardoso Pharmacyst1; Requião-Moura, Lucio R. PhD1; Nakamura, Monica Rika Biomedical1; Lucena, Elizabeth França Biochemistry1; Foresto, Renato Demarchi MD1; Tedesco-Silva, Helio PhD1; Cristelli, Marina Pontello PhD1

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doi: 10.1097/TP.0000000000004029

In the absence of effective therapies, the high lethality and the poor immune response to the available severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have triggered the use of booster doses in patients receiving pharmacologic immunosuppression. The increased immunogenicity of a third dose of messenger RNA vaccines has been demonstrated in recipients of solid organ transplants.1,2

CoronaVac, an inactivated whole-virus vaccine, has been used in over 40 countries, showing high effectiveness for the prevention of coronavirus disease 2019 (COVID-19)–associated death.3,4 In this analysis from an ongoing phase 4 prospective, interventional, single-center study (NCT04801667), we report the immunogenicity and breakthrough infections after the third homologous dose of CoronaVac in kidney transplant recipients without a humoral response after the standard 2-dose schedule.

Between March 17, 2021, and April 25, 2021, 3371 kidney transplant recipients were enrolled and 3340 completed the standard 2-dose vaccine schedule. Immunogenicity was evaluated in a subset of patients randomly selected as described elsewhere,5 using immunoglobulin G (IgG) antibodies against the receptor-binding domain (AdviseDx SARS-CoV-2 IgG II assay, Abbott Laboratories; lower limit of positivity 50 AU/mL). The seroprevalence of IgG–anti–SARS-CoV-2 was 15% 28 d after the first dose and 43% 28 d after the second dose in the immunogenicity cohort (n = 942; Figure S1, SDC,

Of the 484 patients who were seronegative 28 d after the second dose of the vaccine, 326 received the third dose after a median of 79 d (interquartile range [IQR], 74–81 d), and no serious adverse event was reported until the last follow-up date, September 22, 2021. Of the 158 who did not receive the third dose, 6 had died from COVID-19, 15 had acute SARS-CoV-2 infection, 1 had already received a booster dose of heterologous vaccine, 7 refused to receive a third dose, and 129 did not show up. The median age of these 326 patients was 51 y (IQR, 45–57 y), 189 (58%) were male, and the median time from transplant was 72 mo (IQR, 32–131 mo). The main immunosuppressive regimen was tacrolimus, mycophenolate, and prednisone (133, 41%). Twenty patients did not have follow-up serology (Figure S1, SDC, and 6 patients had seroconverted immediately before the third dose. Among the 300 patients with confirmed seronegative IgG–anti–SARS-CoV-2 test immediately before the third dose, only 61 (20.3%) showed seroconversion 28 d after the third dose (Figure 1).

Abbott AdviseDx 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 LoD by the manufacturer is 6.8 AU/mL (0.83 log), and the analytical measuring interval is 21 (1.32 log, LoQ) to 40 000 (4.60 log) AU/mL. The threshold for considering the test as positive is 50 AU/mL or 1.69 log (black line). Immunogenicity analysis from the 326 patients vaccinated with 3 homologous doses of inactivated whole-virion CoronaVac vaccine (306 of whom with 3 sequential measures). After the second dose (D2, pink), 197 (60%) individuals had antibody titers below LoD; among those with detectable values, the median titers were 19 AU/mL (IQR 11–30 AU/mL), but all below 50 AU/mL. Before the third dose (D3, blue), 189 patients remained with undetectable antibody titers and the median titers among those with detectable values were 16 AU/mL (IQR, 11–25 AU/mL). Six patients seroconverted between D2 and D3. After the third dose (D4, orange), 141 (46%) subjects still had undetectable antibody titers; in those with detectable values, the median titers was 34 AU/mL (IQR, 15–97 AU/mL). Seroconversion occurred in 61 (20%) patients (median 21 AU/mL [IQR, 13–35 AU/mL] at D3 and 160 AU/mL [IQR, 90–343 AU/mL] at D4). IgG, immunoglobulin G; IQR, interquartile range; LoD, lowest limit of detection; LoQ, limit of quantification; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

As of September 22, 2021, 18 (5.5%) patients who received the third dose developed SARS-CoV-2 infection, 13 of them beyond 15 d after the third dose. In 9 of them, IgG–anti–SARS-CoV-2 test 28 d was obtained after the third dose and before the COVID-19, and all were negative (<50 AU/mL). There were 9 hospital admissions out of the 13 patients with >15 d after the third dose, 6 needed mechanical ventilation and 4 ultimately died, yielding a lethality rate of 30%. Two of the 4 patients who died had serology collected after the third dose of vaccine; in both cases, the antibody titers were undetectable.

Altogether, these data demonstrate that a third dose of homologous inactivated whole-virion vaccine administered to kidney transplant recipients seronegative after the standard 2-dose regimen was associated with a small increase in seroconversion, low antibody titer and lack of evident clinical effectiveness. Preventive strategies using additional doses of homologous and heterologous vaccines are warranted.


1. Hall VG, Ferreira VH, Ku T, et al. Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients. N Engl J Med. 2021;385:1244–1246.
2. Kamar N, Abravanel F, Marion O, et al. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385:661–662.
3. Jara A, Undurraga EA, González C, et al. Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile. N Engl J Med. 2021;385:875–884.
4. Wilder-Smith A, Mulholland K. Effectiveness of an Inactivated SARS-CoV-2 Vaccine. N Engl J Med. 2021;385:946–948.
5. Medina-Pestana J, Cristelli MP, Viana LA, et al. Clinical impact, reactogenicity, and immunogenicity after the first coronavac dose in kidney transplant recipients. Transplantation. [Online ahead of print. July 20, 2021]. doi:10.1097/TP.0000000000003901

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