Inactivated Whole-virus Vaccine Triggers Low Response Against SARS-CoV-2 Infection Among Renal Transplant Patients: Prospective Phase 4 Study Results

ABSTRACT

1. Background

Anti-severe acute respiratory syndrome coronavirus 2 mRNA vaccines elicit lower humoral responses in solid organ transplant recipients. This is the first prospective trial investigating the effect of an inactivated whole-virion vaccine in kidney transplant recipients.

2. Methods

Prospective, single-center, phase 4, interventional study. Kidney transplant recipients aged 30–69 y with >30 d of transplantation received two 3 µg intramuscular doses of CoronaVac 28 d apart and are being followed for 6 mo. Primary outcomes: (1) reactogenicity after the first dose; (2) antibody responses 28 d after each dose; and (3) incidence/ severity of confirmed coronavirus disease 2019 (COVID-19) and 28-d lethality rate. For this analysis, clinical effectiveness was assessed for 3 mo, starting 15 d after the second dose, and compared with a 3-mo period before vaccination.

3. Results

Of the 3371 individuals who received the first dose, 99% completed the vaccination schedule. Mild/local adverse reactions were reported by 33% of the patients. In the immunogenicity cohort (n = 942), the proportion of patients with IgG antibodies to severe acute respiratory syndrome coronavirus 2 increased from 15.2% after the first dose to 43% after the second dose. An increase in antibody values after the second dose was associated with a higher proportion of patients with detected neutralizing antibodies. A significant reduction in the incidence of COVID-19 was observed (6.4% versus 4.2%; P < 0.0001), although the 28-d lethality rate remained unchanged (25% versus 22%; P = 0.534). In 45 patients from the immunogenicity cohort who developed COVID-19, all 6 deaths occurred among those without antibody response (n = 22; 49%).

4. Conclusions

The coronaVac vaccine was associated with low reactogenicity and low immunogenicity but a reduced incidence of COVID-19 among kidney transplant recipients. The lack of reduction in lethality rates is perhaps associated with the low percentage of patients developing humoral responses after the second dose.

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INTRODUCTION

Mass vaccination campaigns are expected to change the coronavirus disease 2019 (COVID-19) pandemic’s impact on society, an unprecedented situation that has already led to the death of >4 million people on all continents by July 2021.1 Vaccines from several platforms have been developed in record time, among them is CoronaVac (Sinovac Life Sciences, Beijing, China), an inactivated whole-virion vaccine approved by the World Health Organization for emergency use that has already had >750 million doses distributed in >40 countries and that will now also be distributed through the COVID-19 vaccines global access initiative, especially to low-income countries.2,3 In addition, a real-life study involving >10 million Chileans4,5 showed an effectiveness of 65.9% in preventing COVID-19 in the general population, confirming the previous results of clinical trials.6,7

Kidney transplant recipients constitute a highly vulnerable subgroup of individuals. The accumulation of comorbidities and the continuous and unavoidable state of pharmacological immunosuppression lead to an increased risk of developing severe forms of COVID-19.8,9 Furthermore, to date, available data report that only 34%–48% of patients develop antibody response 4wk after the traditional 2-dose scheme of mRNA or viral vector vaccines.10-13

The studies already published observed small groups of patients who have been vaccinated as part of a local immunization program, used a variety of different assays to detect anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, covered a short observation period (maximum 4wk after the second dose), and did not systematically investigate vaccine breakthrough infection. In this interventional study that recruited a large cohort of patients, we report data on reactogenicity, immunogenicity, and clinical effectiveness over a 3-mo period following the full 2-doses vaccine schedule. Furthermore, we analyzed the clinical effectiveness of the vaccine comparing the COVID-19 incidence and outcomes of fully vaccinated kidney transplant recipients versus a control group of unvaccinated ones.

PATIENTS AND METHODS

1. Study Design

This is an ongoing prospective, single-center, phase 4, interventional study assessing the reactogenicity, immunogenicity, and clinical effectiveness of a whole-virion inactivated vaccine to prevent SARS-CoV-2 infection and its associated mortality among kidney transplant recipients. All patients will be followed for 6 mo after the administration of the last dose of the vaccine. The study was approved by the local ethics committee, and all enrolled patients provided written informed consent. The study has been conducted following the Declaration of Helsinki and Good Clinical Practices and is registered at ClinicalTrials. gov (NCT04801667).

2. Inclusion Criteria Kidney transplant recipients aged 30–69 y, with >30 d of transplantation, living within 200 km from the transplant center, and able to participate in all of the study procedures were eligible for enrollment.

3. Exclusion Criteria

Patients with a previously confirmed SARS-CoV-2 infection, those who have previously received any vaccine against SARS-CoV-2, or any other vaccine in the previous 4wk were excluded. Also, individuals who had received blood-derived products or intravenous globulins in the previous 4wk, those with previous history of angioedema or anaphylactic reactions to vaccines, pregnant women, under current treatment for neoplasia, with a medical history of coagulopathy, and uncontrolled psychiatric illness were not eligible.

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4. Study Procedures

The participants were scheduled to receive the standard 2-dose inactivated whole-virion CoronaVac (3 µg, each dose, intramuscular route) vaccine. The vaccination took place at the transplant center on 4 weekends (first dose on March 20, 21, 27, and 28, 2021; second dose on April 17, 18, 24, and 25, 2021), with approximately 800–900 appointments per day.14

Patients were instructed to seek the Tele-Assistance center, which had been in operation since the beginning of the pandemic,15 in case of any symptoms, any time after vaccination. A dedicated group followed those with the confirmed diagnosis and were referred to local hospitals for COVID-19 treatment when indicated. Confirmed COVID-19 was defined as flu-like symptoms combined with a positive nucleic acid amplification-based or antigen testing obtained during the symptomatic period. For this analysis, the final follow-up date was August 22, 2021 (28 d after the last patient with confirmed COVID-19).

5. Reactogenicity

Data on the reactogenicity were obtained from all patients who received the first dose of the CoronaVac vaccine using a prespecified questionnaire applied on the day of the second dose administration (D1 study visit).

6. Immunogenicity

Blood samples were collected from all patients before the first dose (D0) to assess IgG against the SARS-CoV-2 nucleoprotein using the Abbott SARS-CoV-2 IgG assay as a screening test. In a subset of patients labeled as immunogenicity cohort additional samples were collected before the second dose (D1) and at least 28 d after the second dose (D2). This minimum sample size of the immunogenicity cohort (n = 726) was calculated based on the age distribution and seroconversion rate (71%) observed in the phase 3 trial conducted in healthcare professionals,7 with a 95% confidence interval (CI) and an absolute error of 10%. Patients with a positive IgG anti-SARS-CoV-2 at D0 were not eligible for this analysis. IgG antibodies to the receptor binding domain of the S1 subunit of the spike protein of SARS-CoV-2 were assessed at D1 and D2 study visits using the AdviseDx SARS-CoV-2 IgG II assay (Abbot Laboratories, IL). Values >50 arbitrary units (AUs)/mL were considered positive.16

7. Exploratory Analysis of the Neutralization Activity

In a subgroup of patients of the immunogenicity cohort, we explored the association between IgG value and the detection of neutralizing anti-SARS-CoV-2 antibodies (≥30% signal inhibition using the class SARSCoV-2 Neutralization Antibody Detection Kit—GenScript Laboratories).17 The proportion of patients with detected neutralizing anti-SARS-CoV-2 antibodies was analyzed in 2 groups, the first group showing no changes (n = 15) and the second group with the highest changes (n = 15) in IgG values measured after the first and after the second vaccine dose.

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8. Clinical Effectiveness Analysis

The effectiveness of the vaccine was evaluated by comparing the incidence of COVID-19 per 1000 patients at risk 3 mo before the study (unvaccinated control group) with that observed during the following 3 mo, starting 15 d after the second dose, using an interrupted time series analysis.18 Only patients with at least 28 d of follow-up since the diagnosis were included in this analysis in both periods.

For the unvaccinated control group, the persons at risk were all unvaccinated kidney transplant recipients aged between 30 and 69 y living in the transplant center state, alive, and with functioning grafts on December 20, 2020. Those with symptomatic SARS-CoV-2 infection confirmed by reverse transcription polymerase chain reaction or antigen test between December 20, 2020, and March 19, 2021, were included as COVID-19 cases. For the fully vaccinated group, the persons at risk were all fully vaccinated individuals who were alive, with functioning grafts, and no confirmed COVID-19 up to May 10, 2021 (15 d after the second vaccine dose administration). Those with symptomatic SARS-CoV-2 infection confirmed by reverse transcription polymerase chain reaction or antigen test after May 10, 2021, and until July 24, 2021, were included as COVID-19 cases.

The number of new kidney transplants, deducting the loss of follow-up and deaths from other causes, in each week in both periods, was not included in the analysis, as the net number that would be added to the denominator would be quite small and unlikely to interfere with the assessment of the incidence rates.

9. Clinical Outcomes

The primary outcomes were the incidence of confirmed COVID-19/1000 persons at risk, the need for hospitalization and mechanical ventilation, and 28-d lethality rates at least 15 d after the second vaccine dose. Secondary outcomes were the incidence of COVID-19, hospitalization, mechanical ventilation, and 28-d lethality rates after the first dose, <15 d, and >15 after the second dose.

10. Statistical Analysis

Categorical variables were reported as frequencies and percentages. Continuous variables were presented as median and interquartile ranges (IQRs). Multivariable binary logistic regression was used to identify clinical variables independently associated with seroconversion after the second dose of CoronaVac and with 28-d mortality. Variables with P < 0.10 or at the discretion of the investigator in the univariable analysis were included in the multivariable model using a backward conditional selection procedure. Results were expressed as odds ratios (ORs) with their 95% CI. The effectiveness was obtained by comparing the COVID-19 incidence rates before and after the vaccination using the interrupted time-series analysis. The intervention of interest was set at 15 d after the second dose of CoronaVac. Differences or effects were considered significant with a P < 0.05. Statistical analysis was performed using the SPSS program v. 22.0 (SPSS Inc, Chicago, IL) and GraphPad Prism program v.9.2.0 (Prisma Inc, CA).

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DISCUSSION

In this prospective, phase 4, nonrandomized, and single-center study involving 3371 kidney transplant recipients, administration of a 2-dose regimen of CoronaVac vaccine was associated with low reactogenicity and an increase in the seroconversion rate from 15% after the first dose to 43% after the second dose.

The observed low antibody response is congruent with already published data on mRNA and adenovirus vectored vaccines reporting seroconversion between 3% and 59%, depending on the characteristics of the study population and the time of evaluation.10,19 In agreement with this information, a Saxon study involving over 3100 participants between general population, hemodialysis, and transplant patients noted that not only the humoral response but the frequency of SARS-CoV-2 reactive CD4+ T helper cells producing Th1 cytokines is significantly reduced among transplant recipients,20 which reinforces the hypothesis that a high proportion of these individuals remains vulnerable to infection even after vaccination.

Similar to what was found in the phase 3 study involving 9823 healthcare workers vaccinated with CoronaVac,7 older age was the main factor related to the lack of vaccine response, with a 4% reduction in the odds of seroconversion for each additional year. Being a deceased donor transplant recipient was also a risk factor independently associated with a lack of response, and it is plausible to speculate that this variable represents an indirect marker of the recipient’s frailty, including older age, higher comorbidities, and longer time on dialysis.21 Contrary to previously described,11,12 the immunosuppressive regimen was not associated with seroconversion. However, most of our patients were on triple immunosuppression with a calcineurin inhibitor, steroids, and antimetabolite, limiting further comparative analyses.

There was a significant reduction in the incidence of COVID-19 starting from 2wk after the second dose compared to the 3-mo period before the study. Although this finding may have been related to seroconversion, caution should be exercised in attributing a causal relationship, as the period of improvement coincides with the adoption of more intense restrictive and physical distancing measures, an increasing percentage of the vaccinated population (reaching 74% of the inhabitants with at least 1 dose and 33% with the complete schedule at August 22, 2021) and a decline in the overall number of new cases of COVID-19 in the state of Sao Paulo. For context, in the period between December 20, 2020, and March 19, 2021, the local incidence of new confirmed cases of SARS-CoV-2 infection increased from 0.09 (week 52/2020) to 0.21 (week 11/2021) cases/1000 patients at risk per week. From May 10, 2021, to July 24, 2021, this rate went up from 0.17 (week 18/2021) to 2.0 (week 22/2021), then declined to 0.13 cases/1000 patients at risk per week in the epidemiological week 29/2021.22

Compared with the unvaccinated control group, there was no reduction in 28-d lethality associated with COVID-19. However, developing COVID-19 15 d after the second vaccine dose was associated with a lower risk of lethality in multivariate analysis. Furthermore, there were no deaths among those who had developed a humoral response in a small subgroup of patients with known postvaccination seroconversion status who subsequently acquired COVID-19.

Limitations of the study include the absence of a randomized control group, potentially receiving another type of vaccine, the underrepresentation of patients receiving alternative immunosuppressive drug combinations, the investigation of neutralizing activity in a small cohort, and the lack of data on cellular immunity. On the other hand, the strengths of the study include the prospective and systematic observation of a large number of patients, the homogeneity of the serological tests, and the extended follow-up time.

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In summary, the results also point to low reactivity and immunogenicity of the inactivated whole-virion vaccine among kidney transplant patients. Vaccination was associated with a reduction in the incidence of SARSCoV-2 infection, possibly related to seroconversion and lower circulation of the virus in the general population. Nevertheless, overall lethality was unchanged and possibly related to a lack of seroconversion. Thus, strategies seeking seroconversions, such as additional doses, modified concentrations, use of other adjuvants, or vaccine combinations, should be urgently pursued in the high-risk population.

REFERENCES

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7. Palacios R, Batista AP, Albuquerque CSN, et al. Efficacy and safety of a COVID-19 inactivated vaccine in healthcare professionals in Brazil: the PROFISCOV study. SSRN. Available at http://dx.doi.org/10.2139/ ssrn.3822780. Accessed August 8, 2021.

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9. Cristelli MP, Viana LA, Dantas MTC, et al. The full spectrum of COVID-19 development and recovery among kidney transplant recipients. Transplantation. 2021;105:1433–1444.

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11. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-Dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325:2204–2206.

12. Marion O, Del Bello A, Abravanel F, et al. Safety and immunogenicity of anti-SARS-CoV-2 messenger RNA vaccines in recipients of solid organ transplants. Ann Intern Med. 2021;325:2204–2206.

13. Benotmane I, Gautier-Vargas G, Cognard N, et al. Low immunization rates among kidney transplant recipients who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine. Kidney Int. 2021;99:1498–1500.

14. Medina-Pestana J, Cristelli MP, Viana LA, et al. Clinical impact, reactogenicity, and immunogenicity after the first CoronaVac dose in kidney transplant recipients. Transplantation. 2022;106:e95–e97.

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16. Abbott Laboratories. AdviseDx SARS-CoV-2 IgG II instructions for use. 2021. Available at https://www.fda.gov/media/146371/download. Accessed August 23, 2021.

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José Medina-Pestana, PhD,1 Dimas Tadeu Covas, PhD,2,3 Laila Almeida Viana, MD,1 Yasmim Cardoso Dreige, PharmB,1 Monica Rika Nakamura, BS,1 Elizabeth França Lucena, PharmB,1 Lucio R. Requião-Moura, PhD,1 Carlos Magno Castelo Branco Fortaleza, PhD,4 Renato Demarchi Foresto, MD,1 Helio Tedesco-Silva, PhD,1 and Marina Pontello Cristelli, PhD1

1 Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.

2 Instituto Butantan, São Paulo, Brazil.

3 Center for Cell-based Therapy (CTC), Regional Blood Center of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

4 Infectious Diseases Division, Universidade Estadual Paulista (UNESP), Botucatu, Brazil.